Certain 1H-pyrrold[3,4-b]quinolin-1-one-9-amino-2,3-dihydro derivatives useful for treating anxiety

ABSTRACT

The present invention comprises certain quinoline lactams of formula I; pharmaceutically acceptable salts of the compounds of formula I; pharmaceutical compositions containing a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of anxiety; and processes for the manufacture of the compounds of formula I, as well as intermediates for use in such manufacture.

SUMMARY OF THE INVENTION

The compounds of the invention are heterocyclic fused tricyclics withselected side chain substitutions on the A and C rings, which are usefulas agents for binding to benzodiazepine receptors, and which may also beused as biochemical tools.

DETAILED DESCRIPTION OF THE INVENTION

Selected tricyclic compounds described as memory enhancers are describedin EPO Publication No. 0,179,383 to Shutske et al. Selected tricyclicpyrazolopyridines are disclosed in U.S. Pat. Nos. 4,511,568 to Bare etal and 4,546,104 to Campbell et al (both of which are assigned to thesame assignee as this application). Quinoline compounds may be seen inEPO Publications Nos. 0,205,362 to Keane et al and 0,070,767 to LeMartret and U.S. Pat. No. 4,450,167 to Le Martret et al.

The compounds of the invention are tricyclics of formula I:

    (Formula set out on pages following Example)               I

where ring A is a 5 or 6 membered aromatic ring selected from the groupconsisting of the members shown in formulae Ia-Ie:

    (Formulae set out on pages following Examples)             Ia, Ib, Ic, Id, Ie

wherein:

n=1 or 2;

X=>C-H or N:

Y=O, S, or >N-Rd; and

where > indicates two bonds;

Ra is selected from a group consisting of (1-10C)alkyl, (3-10C)alkenyl,(3-10C)alkynyl, (3-7C)-cycloalkenyl, (4-7C)cycloalkenyl,(4-10C)cycloalkylalkyl (5-9C)alkylidenecycloalkylalkyl, (1-4C)alkoxy,(1-4C)alkylthio, (2-10C)hydroxyalkyl, (4-10C)hydroxycycloalkylalkyl,(2-10C)ketoalkyl, (1-10C)haloalkyl and (3-10C)haloalkenyl having atleast one halo group wherein the halo group(s) is independently selectedfrom a group consisting of fluoro and chloro, (6-10C)-aryl,(7-12C)arylalkyl (wherein said aryl portion of the aryl or arylalkylmay, optionally, be substituted by a member selected from a groupconsisting of (1-4C)alkyl, (1-4C)alkoxy, halogeno, and amino optionallysubstituted independently by one or two of (1-4C)alkyl), and wherein thealkyl portion of the arylalkyl may optionally be substituted by hydroxy,a heteroaryl having a 5 or 6-membered ring wherein said ring containsone or more heteroatoms independently selected from a group consistingof sulfur, oxygen and nitrogen and wherein the heteroaryl may optionallybe substituted by (1-3C)alkyl, a heteroaryl(1- 3C)alkyl having a 5 or6-membered ring wherein said ring contains 1-3 heteroatoms independentlyselected from a group consisting of sulfur, oxygen and nitrogen andwherein the heteroaryl may optionally be substituted by (1-3C)alkyl;

Rb is selected from a group consisting of hydrogen, (1-10C)alkyl(optionally substituted by (1-3C)alkoxy), (3-7C)cycloalkyl,(4-10C)cycloalkylalkyl, (3-8C)alkenyl, (3-8C)alkynyl, (2-8C)haloalkylhaving 1-3 halo group(s) independently selected from fluoro and chloro,(2-8C)haloalkenyl having 1-3 halo group(s) independently selected fromfluoro and chloro, (2-8C)hydroxyalkyl,phenyl, phenyl (1-3C)alkyl,(wherein the phenyl portion of phenyl or phenylalkyl is optionallysubstituted by a member selected from a group consisting of halogeno,(1-3C)alkyl and (1-3C)alkoxy), a 5 or 6 membered heteroaryl orheteroaryl(1-3C)alkyl, containing 1, 2, or 3 members selectedindependently from a group consisting of sulfur, oxygen and nitrogen,wherein the aryl portion of the aryl or arylalkyl may optionally besubstituted by (1-3C)alkyl;

Rc is selected from a group consisting of hydrogen, (1-10C)alkyl and(2-10C)alkanoyl;

Rd is independently selected from the group defined for Rc:

and salts, for example and especially pharmaceutically acceptable saltsthereof.

Particular values for Ra include (1-6C)-alkyl, (3-7C)cycloalkyl,(4-7C)cycloalkenyl, (4-8C)cycloalkylalkyl, (1-4C)alkoxy,(1-4C)alkylthio, (3-6C)alkenyl, (3-6C)alkynyl, (6-10C)aryl,(7-12C)arylalkyl (wherein the aryl portion of the aryl or arylalkyl mayoptionally be substituted by (1-3C)alkyl, (1-3C)alkoxy, halogeno, oramino optionally substituted independently by 1 or 2 of (1-3C)alkyl, andwherein the alkyl portion of the arylalkyl may optionally be substitutedby hydroxy); (1-6C)haloalkyl having at least one of fluoro or chloro,(3-6C)hydroxyalkyl, (4-8C)hydroxycycloalkylalkyl, a 5 or 6-memberedheteroaryl or substituted heteroaryl having 1 or 2 heteroatoms (whereinthe substitution is (1-3C)alkyl), a 5 or 6-membered ring heteroarylalkylhaving 1 or 2 heteroatoms, optionally substituted by (1-3C)alkyl.

Particular values for Rb include (2-5C)alkyl optionally substituted by(1-3C)alkoxy, (3-5C)-alkenyl, (3-5C)alkynyl, (4-6C)cycloalkylalkyl,(3-5C)-haloalkenyl having 1-3 halo group(s), phenyl, phenyl(1-3C)alkyl,(wherein the phenyl portion of phenyl or phenylalkyl is optionallysubstituted by a member selected from a group consisting of halogeno,(1-3C)alkyl and (1-3C)alkoxy), a 5 or 6 membered heteroaryl orheteroaryl(1-3C)alkyl, containing 1 or 2 members selected independentlyfrom a group consisting of sulfur, oxygen and nitrogen, wherein the arylportion of the aryl or arylalkyl may optionally be substituted by(1-3C)alkyl;

Particular values for Rc include hydrogen, (1-6C)alkyl and(2-6C)alkanoyl.

A particular value for Rd is hydrogen.

More particular values for compounds of formula I include those where Ais selected from formula Ia, Ib, Ic and Id, preferably Ia.

More particular values for Ra include (1-6)alkyl, (4-8C)cycloalkylalkyl,(3-6C)alkenyl, (3-6C)alkynyl, phenyl, phenyl(1-2C)alkyl (wherein thephenyl or phenyl portion of the phenylalkyl may optionally besubstituted by a member selected from a group consisting of fluorine,chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, andamino optionally substituted independently by 1 or 2 of (1-3C)alkyl, andwherein the alkyl portion of the phenylalkyl may optionally besubstituted by hydroxy), heteroarylalkyl selected from a groupconsisting of 2-thienylmethyl, 3-thienylmethyl,N-methyl-2-pyrrolylmethyl, 2-thiazolylmethyl, 2-oxazolylmethyl,3-pyridylmethyl and 4-pyridylmethyl.

More particular values for Rb include (2-5C)alkyl optionally substitutedby (1-3C)alkoxy, (3-5C)alkenyl, (3-5C)alkynyl, (4-6C)cycloalkylalkyl,benzyl optionally substituted on the phenyl by a member selected from agroup consisting of fluorine, chlorine, bromine, (1-3C)alkyl and(1-3C)alkoxy; and a heteroalkylalkyl selected from 2-furylmethyl.

More particular values for Rc include hydrogen, propyl, butyl, acetyl,butyryl and valeryl.

Even more particular values for the above described groups are asfollows:

Ra: methyl, ethyl, n-propyl, n-butyl, 3-methylbutyl, n-pentyl,2-methylbutyl, 2,2-dimethylpropyl, 2-methylpropyl,3-trifluoromethylbutyl, 4,4,4-trifluorobutyl, 1-hydroxy-3-methylbutyl,1-hydroxypropyl, 3-butenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl,3-pentynyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-thienylmethyl, 3-thienylmethyl, benzyl, phenethyl, 4-fluorobenzyl,1-hydroxy-1-phenylmethyl, phenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, 4-methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl,4-dimethylaminophenyl;

Rb: ethyl, n-propyl, n-butyl, 2-methoxyethyl, 3-methoxypropyl,2-propenyl, 2-propynyl, 2-butynyl, cyclopropylmethyl, benzyl,2,4-dimethoxybenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-methoxybenzyl,4-chlorobenzyl, 3-methoxybenzyl, 2-fluorobenzyl and 2-furylmethyl;

Rc: hydrogen;

and these compounds are further useful as anxiolytics.

Preferably compounds of formula I are selected to be those whereinX=nitrogen and n=1. Rb is preferably chosen to be propyl, butyl or2-propenyl.

Preferred compounds of the invention are those of formula I as follows:(a) A is selected as formula Ia with n=1, X=nitrogen, Ra=3-methylbutyl,Rb=propyl and Rc=hydrogen; (b) A is selected as formula Ia with n=1,X=nitrogen, Ra=2-methylpropyl, Rb=propyl and Rc=hydrogen; (c) A isselected as formula Ia with n=1, X=nitrogen, Ra=cyclopropylmethyl,Rb=propyl and Rc=hydrogen; and most preferably (d) A is selected asformula Ia with n=1, X=nitrogen, Ra=propyl, Rb=propyl and Rc=hydrogen.

It will be appreciated that certain of the compounds of this inventionmay contain an asymmetrically substituted carbon atom, and may exist in,and be isolated in, optically-active and racemic forms In addition, itwill be appreciated that certain compounds of this invention may existin and be isolated in, separate stereoisomeric forms (`E` and `Z`) aboutthat group. Some compounds may exist in more than one tautomeric form.Some compounds may exhibit polymorphism. It is to be understood that thepresent invention encompasses any racemic, optically-active, tautomeric,polymorphic or stereoisomeric form, or mixtures thereof, which formpossesses benzodiazepine binding properties, it being well known in theart how to prepare optically-active forms (for example, by resolution ofthe racemic form or by synthesis from optically-active startingmaterials) and individual `E` and `Z` stereoisomers (for example, bychromatographic separation of a mixture thereof) and how to determinethe benzodiazepine binding properties by the standard tests describedhereinafter.

In this specification Ra, Rb, et cetera stand for generic radicals andhave no other significance. It is to be understood that the generic term"(1-6C)alkyl" includes both straight and branched chain alkyl radicalsbut references to individual alkyl radicals such as "propyl" embraceonly the straight chain ("normal") radical, branched chain isomers suchas "isopropyl" being referred to specifically. A similar conventionapplies to other generic groups, for example, "alkylene" and"alkenylene" et cetera. Halogeno or halo is fluoro, chloro, or bromo.

The salts of the compounds of formula I are preferably thepharmaceutically acceptable salts, but other salts may, for example,find use in the preparation of the compounds of formula I and thepharmaceutically acceptable salts thereof.

A particular pharmaceutically acceptable acid addition salt is oneformed with hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acidor methane sulfonic acid.

Compounds of formula I may be prepared by using methods known in partfor the preparation of chemically similar compounds. Thus the followingprocesses are provided as a further feature of the invention:

(a) Compounds of formula I in which Rc is hydrogen may be prepared bycyclization of a compound of formula II:

(Formula set out on pages following Examples) II for example, in amanner similar to that described in U.S. Pat. Nos. 4,511,568 and4,546,104 using cyclization catalysts which may include (CH₃)₃ Al, CuO₂CCH₃, ZnCl₂, ZnBr₂, NaH/CdCl₂ and at a temperature of ambient to 120°.

(b) Compounds of formula I, in which A is selected from formula Ia, Iband Ic and in which Rc is hydrogen and Ra is a group of formula CH₂ Re(where Re has the value as defined below), may be prepared by alkylationand cyclization, for example in a sequential single potalkylation-cyclization, of a compound of formula IIa,

(Formula set out on pages following Examples) Ila which A¹ has thevalues as defined for A except that Ra=--CH₂ Cl, by reaction with analkylating agent (Re)_(p) M, preferably at about 0° to ambienttemperature for the alkylation step, preferably followed by heatingtobout 40°-70° to effect cyclization. Re is selected from a groupdefined for Ra in which a --CH₂ -- has been removed at the point ofattachment to the A ring and provided that Re must be selected so thatit is possible to remove a --CH₂ --; thus Re may not be selected to befrom those defined for Ra such as aryl, heteroaryl, cycloalkyl, alkenylor alkynyl where the multiple bond is on the carbon attached to the Aring, et cetera; M is selected from a group consisting of zinc, cadmiumand titanium; p has a value of 2 when M=Zn or Cd and a value of 4 whenM=Ti;

(c) For those compounds of formula I, where A=formula Ia in which Ra is,for example, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, or substituted aryl (wheresubstitution is alkyl, halogeno, alkoxy, or dialkylamino), thesecompounds may be made by reacting an organometallic derivative of thecompound RaX in which X is a halogen (for example an organozincreagent), with that compound of formula I where A=formula Ia in which Rais initially bromine or iodine, preferably at about ambient to 70° C.,in the presence of a suitable transition metal catalyst (for example,dichloro-[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)).

Compounds of formula I in which Rc is hydrogen, A is of formula Ia andRa is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,(cycloalkyl)alkyl, aryl, or substituted aryl, may be prepared by thedeprotection of a compound corresponding to a compound of formula I, butin which NHRc is replaced by NHP in which P represents an amineprotecting group. The protecting group is preferably a trifluoroacetylgroup which may be removed by the use of a base as described herein. Aprotecting group may be used, for example, in certain cases milderreaction conditions may be employed by first reacting compounds of theformula I where A=formula Ia in which Ra is initially bromine or iodine,with trifluoroacetic anhydride in the presence of a base such as sodiumhydride. The resulting N-trifluoracetylated compound may then be reactedwith an organometallic derivative of compound RaX in which X is ahalogen (for example an organozinc reagent) at ambient temperature inthe presence of a suitable transition metal catalyst such as thosedescribed above. The resulting compound (after treatment with base inalcohol) (for example KOH in methanol) gives the substituted compoundsof formula I where A=formula Ia.

(d) For those compounds of formula I where A is formula Ia in which Rais 1-hydroxyalkyl or 1-hydroxyaryl, these compounds may be made byreacting an organometallic derivative of formula ReX in which X is ahalogen (for example organolithium or a Grignard reagent) with acompound of the formula I where A is formula Ia and Ra is formyl.Compounds of formula I where A is formula Ia and Ra is formyl may beprepared by ozonolysis of compounds where Ra is 1-alkenyl.

(e) Compounds of formula I in which A is selected to be formula Ib withY=S and Rc=hydrogen may be prepared by reaction of a compound of formulaIII: (Formula set out on pages following Examples) III where Z is chloroor ethoxy with ammonia;

(f) Compounds of formula I in which Rc is alkanoyl may be prepared byacylation of a compound of formula I in which Rc is hydrogen; and

(g) Compounds of formula I in which Rc is alkyl may be prepared byalkylation of a compound of formula I in which Rc is hydrogen.

Process (a) is the preferred method for synthesis of compounds offormula I. The starting material of formula II for process (a) may beprepared by condensation of the appropriate aminonitrile of formula IV:

    (Formula set out on pages following Examples)              IV

with a compound of formula V:

    (Formula set out on pages following Examples)              V

The compounds of formula V when X=N may be made as described in U.S.Pat. No. 4,511,568 (See the description of compound XIV containedtherein.) The compounds of formula V when X=>C--H may be made asdescribed in U.S. Pat. No. 4,546,104 (see the description of compoundIII contained therein.)

Compounds of formula IV where A is selected to be formula Ia may beprepared according to the procedures described by Marvel, et al, Org.Synthesis, Collect. Vol. I, page 327 (1951), and Bedford et al, J. Chem.Soc., pages 1633-1634 (1959).

Compounds of formula IV where A is selected to be formula Ia may also beprepared according to an improved variation of the synthesis describedby Bedford et. al. (supra). Thus, treatment of the isatin oximesdescribed by Bedford with trifluoromethanesulfonic anhydride in thepresence of a hindered amine base, for example, 2,6-lutidine, followedby addition of a bicyclic amidine base, for example,1,8-diazabicyclo[5.4.0]undec-7-ene then hydrolysis in dilute aqueousbase (for example, sodium bicarbonate), all at ambient temperature,gives compounds of the formula IV where A is selected to be formula Ia.

Compounds of formula IV where A is selected to be formula Ia in which Rais, for example, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, substituted aryl (wheresubstitution is alkyl, halogeno, alkoxy or dialkylamino) may be made byreacting an organometallic derivative of formula RaX in which X is ahalogen (for example an organozinc reagent) with that compound offormula IV where A is formula Ia in which Ra is initially iodine, in thepresence of a suitable transition metal catalyst (for example,dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)).

Compounds of formula IV where A is selected to be formula Ia and whereRa is methyl, may be prepared from commercially available3-methyl-2-nitrobenzoic acid by first converting it to the amide, thendehydrating the amide to the nitrile with subsequent reduction of thenitro group.

Compounds of formula IV where A is selected to be formula Ic and where Yis >N-Rd may be prepared using the procedure described by Klein et al,Tet. Letters, 22: 25-28 (1981).

Compounds of formula IV where A is selected to be formula Id may beprepared using the procedure described by Yamazaki et al, Chem. andPharm. Bull., 30: 2357-2363 (1982).

A second method for the preparation of the starting material of formulaII where A is selected to be formula Ia comprises a novel process. Thus,3-methyl-2-nitrobenzonitrile is converted by oxidation of the methylgroup to the aldehyde. Subsequent reduction to the3-(hydroxymethyl)-2-aminobenzonitrile gives an intermediate of formulaIV where Ra is hydroxymethyl and A is selected to be formula Ia.Condensation with a compound of formula V followed by conversion ofhydroxy to chloro generates the intermediate of formula IIa. Alkylationof compounds of formula IIa may be effected using diorganozinc ordiorganocadmium reagents of formula (Re)_(p) M at or below ambienttemperature in an inert solvent such as methylene chloride to givecompounds of formula II where Ra is an alkyl group.

The diorganozinc reagents may be prepared according to literatureprocedures employing, for example, either Grignard reagents ororganolithium reagents and anhydrous zinc halide, for example, zincbromide. (See Houben-Weyl, Method. der Organischen Chemie, GeorgeThieme, Volume 13/2a (1973)).

Condensation of methyl 4-amino-5-alkylthiophene-3-carboxylate of formulaVI with cyclic 1,3-dicarbonyl compounds of formula V, followed bybase-catalyzed ring closure affords thieno-tricyclic compounds offormula VII (Formula set out on pages following Examples) VII whereW=OH. These thieno-tricyclics may be converted with SOCl₂ /dimethylformamide to compounds of formula III where Z is chloro or with base andethyl iodide or ethyl bromide to compounds of formula III where Z isethoxy.

Compounds of formula III for use in process (e) may be made as follows:

Methyl 4-amino-5-alkylthiophene carboxylates of formula VI

    (Formula set out on pages following Examples)              VI

may be prepared as described in U.S. Pat. No. 4,317,915. Thus, compoundsof formula VI with Ra as propyl (69% yield), butyl (68% yield) andpentyl (47% yield) were prepared.

Pharmaceutically acceptable acid addition salts may be formed byreacting a compound of formula I with an appropriate acid, for example,by dissolving a compound of formula I in a suitable solvent, adding aselected acid to the solution and recovering the salt. It may be desiredto optionally use a protecting group during all or portions of the abovedescribed processes; the protecting group then may be removed at theappropriate time.

As indicated above, the compounds of the present invention are useful asbinders to benzodiazepine receptors. This may be demonstrated by using atritiated flunitrazepam binding assay (FNB test) (see U.S. Pat. Nos.4,511,568 and 4,546,104.) Compounds capable of binding to benzodiazepinereceptors are known to possess a spectrum of activities which range fromanxiolytic activity to the activity of reversing the action ofbenzodiazapines in the central nervous system. In general, the compoundsof the present invention are believed to possess anxiolytic activity. Itwill be appreciated, however, that compounds will vary in their activitydepending on chemical structure and, thus, compounds of the presentinvention will possess a varying ratio of such above mentionedactivities. Anxiolytic activity may be demonstrated in the Shock-InducedSuppression of Drinking (Rats) Test (SSD) described in PharmacologyBiochemistry and Behavior, 12: 819-821 (1980). This test may be carriedout as follows:

Male rats in the weight range of 200 to 220 g are deprived of water for48 hours and deprived of food for 24 hours before testing. Normally, therats are orally intubated and receive a volume of 5 ml/kg containing theappropriate concentration of test compound (based on mg/kg body weight)in a vehicle of hydroxypropylmethylcellulose (HPMC) 0.5% w/v,polyoxyethylene (20) sorbitan monooleate (Tween 80) 0.1% w/v, anddistilled water. The vehicle control group of rats is also intubated bymouth. A positive control group of rats is orally administered a controldose of 18 mg/kg of chlordiazepoxide. Random selection of the rats isutilized in dosing. The rats are returned to the cage for one hour.Sixty minutes after drug administration, the rat is quietly removed fromits cage and the hind feet wiped with Signa electrode gel made by ParkerLaboratories of Orange, N.J. When intraperitoneal (i.p.) administrationis used, the protocol is identical except that the drugs areadministered in varying concentrations in saline in a volume of 5 ml/kg30 minutes prior to testing. Concentrations ranged from 0.4 to 50 mg/kg.The rat is placed on the floor in the chamber facing the licking tube.The animal is allowed 5 minutes to make 20 licking responses and receivethe first shock (0.5 mA). If this response does not occur, the animal isremoved and eliminated from the study. If 20 licking responses are made,the animal is permitted an additional 3 minutes during which time each20th lick is paired with a 0.5 mA shock. This period is automaticallystarted, counted and terminated. The number of licks and shocks arerecorded. The activity of the compound tested is evaluated by comparingthe mean shocks of the group dosed with the test compound to both themean shocks of the vehicle and positive control groups via a Students't-test In general, an increase in the number of shocks received comparedto the control is indicative of the anti-conflict or anti-anxietyactivity of the compound.

Representative compounds of the present invention typically show resultsin the SSD test indicative of anxiolytic activity.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a tricyclic derivative of theinvention in association with a pharmaceutically-acceptable diluent orcarrier.

The pharmaceutical composition may, for example, be in a form suitablefor oral, rectal or parenteral administration, for which purposes it maybe formulated by means known to the art into the form of, for example,tablets, capsules, aqueous or oily solutions or suspensions, emulsions,dispersible powders, suppositories or sterile injectable aqueous or oilysolutions or suspensions.

A preferred pharmaceutical composition of the invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 0.1 mg and 500 mg of the tricyclicderivative, or one suitable for intravenous, intramuscular orsubcutaneous injection: for example, a sterile injectable containingbetween 0.1% and 10% w/w of the tricyclic derivative.

The pharmaceutical composition of the invention will normally beadministered to mammals such as man for relief of anxiety and tension inthe same manner as that employed for chlordiazepoxide, due allowancebeing made in terms of dose levels for the potency and duration ofactions of the tricyclic derivative of the invention relative tochlordiazepoxide. Thus each individual, will receive an oral dose ofbetween 0.5 mg and 500 mg, and preferably between 0.5 mg and 20 mg, oftricyclic derivative, or an intravenous, subcutaneous or intramusculardose of between 0.5 mg and 100 mg, and preferably between 0.5 mg and 20mg, of the tricyclic derivative, the composition being administered oneto four times per day. The rectal dose will be approximately the same asthe oral dose.

The invention is illustrated but not limited by the following examplesin which temperatures are in degrees Celsius and ambient temperaturerefers to 23°±3°. Chemical symbols have their usual meanings unlessotherwise specified and the following abbreviations are used: ml(milliliter), g (gram), mg (milligram), m.p. (melting point), tlc (thinlayer chromatography), R_(f) (relative mobility in tlc), atmosphericpressure (1.013×10⁵ Pascals/atm), hr. (hour), min. (minute), Ra, Rb etc.are generic radicals and have the meanings stated above unless indicatedotherwise. Unless stated otherwise, ratios of solvents are byvolume/volume, v/v.

In general, no sign of overt toxicity has been observed with compoundsof the invention at dosages at least several multiples of their minimumeffective doses in the SSD test.

EXAMPLE 1 a.9-Amino-2,3-dihydro-5-methyl-2-propylpyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=methyl, Rb=propyl, Rc=H)

The benzonitrile described in Example 1e (0.60 g) was suspended inmethylene chloride (10 ml) maintained at ice bath temperature under anargon atmosphere. Trimethylaluminum (3.48 ml of a 1.35M solution inheptane) was added dropwise to the reaction vessel. After the additionwas completed the cooling bath was removed and the solution was warmedto ambient temperature then heated to gentle reflux (about 45°). Afterheating for 4 hours at reflux, the reaction solution was cooled in anice bath and carefully quenched by adding water dropwise. The mixturewas made basic (pH greater than 9) with 10% aqueous NaOH, then ethylacetate/tetrahydrofuran was added. The organic phase was separated andsuccessively washed with brine, dried (Na₂ SO₄) and concentrated. Thecrude product was chromatographed over silica gel using ethylacetate:hexane (3:7) as the eluent. The resulting white solid wasrecrystallized from acetone/hexane to give the title compound as a whitesolid (210 mg, 35%); m.p. 200°-207° (with decomposition); tlc, R_(f)=0.28, silica gel, ethyl acetate:hexane (1:1): a small impurity wasevident at R_(f) =0.50.

Analysis calculated for: C₁₅ H₁₇ N₃ O: 70.56; H, 6.71; N, 16.45 ; Found:C, 69.51: H, 6.69: N, 16.09.

b. 3-Methyl-2-nitrobenzenecarboxamide

To a solution of 3-methyl-2-nitrobenzoic acid (13.2 g) intetrahydrofuran (150 ml) was added slowly at ambient temperaturetriethylamine (11.0 ml). After stirring for 30 minutes, the solution wascooled in an ice bath and ethyl chloroformate (7.6 ml) was addeddropwise. Following the addition the thick mixture was stirred for 1hour while maintaining the temperature at about 0°. Next, gaseousammonia was bubbled through the well stirred mixture until it was wellsaturated (about 15 minutes). The cooling bath was removed and themixture was allowed to warm slowly to ambient temperature with stirringfor 2 hours. The mixture was partitioned between ethyl acetate andwater; some gentle warming was required to solubilize all of the solidmaterial. The layers were separated; the organic phase was washed withbrine, dried over Na₂ SO₄ and concentrated to leave a white solid.Trituration with ether/hexane followed by filtration afforded thecarboxamide (12.5 g, 95%); m.p. 189°-191°; tlc, R_(f) =0.08, silica gel,ethyl acetate:hexane (1:1).

c. 3-Methyl-2-nitrobenzonitrile

To a mixture of the carboxamide of Example 1b (12.5 g) and pyridine(11.2 ml) suspended in tetrahydrofuran (100 ml) and maintained at icebath temperature was added dropwise trifluoroacetic anhydride (10.7 ml)over a period of 30 minutes. After the addition, the resulting solutionwas warmed to ambient temperature and stirred for 3 hours. Afterremoving the volatiles under aspirator vacuum, the remaining crude solidwas partitioned between equal volumes of ethyl acetate and water. Thelayers were separated: the ethyl acetate layer was washed with brine,dried over MgSO₄ and filtered through a small pad of silica gel. Afterconcentrating the material, the resulting solid was recrystallized frommethylene chloride/hexane to give the title compound as a white solid(10.5 g, 94%); m.p. 74.5°-77°; tlc, R_(f) =0.45, silica gel, ethylacetate:hexane (1:1).

d. 2-Amino-3-methylbenzonitrile (Formula IV, A=formula Ia, Ra=methyl)

The benzonitrile prepared in Example 1c (4.5 g) was hydrogenated over 5%palladium on barium sulfate suspended in ethanol (105 ml) at atmosphericpressure. After filtering through diatomaceous earth to remove thecatalyst, the solution was concentrated to leave a yellow solid (3.79g). Purification by chromatographing the material over silica gel usingether:hexane (7:13) afforded the title product (2.53 g, 69%) as acloudy, yellow oil: tlc, R_(f) =0.44, silica gel, ether:hexane (1:1).

e. 2-(1-Propyl-2-oxo-3-pyrrolin-4-yl )amino-3-methylbenzonitrile(Formula II, A=formula Ia, X=N, Ra=methyl, Rb=propyl, n=1)

Freshly prepared 1-propyl-2,4-dioxopyrrolidine was prepared by heatingtogether 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (1.16 g) (U.S. Pat.No. 4,511,568, Example 52d describes the preparation of the methoxycompound; the ethoxy compound may be prepared in a similar manner), andacetonitrile (100 ml). After heating for 1.5 hours the volatiles wereremoved under aspirator vacuum and the residue consisting of crude2,4-dioxopyrrolidine was taken up in toluene (4 ml). This solution wasadded dropwise to a refluxing mixture of 2-amino-3-methylbenzonitrilefrom Example 1(0.48 g) and p-toluenesulfonic acid (36 mg) in toluene (10ml). The refluxing mixture was surmounted with a Dean-Stark trap tocollect water evolved in the reaction as the azeotrope with toluene.Following the addition of 2,4-dioxopyrrolidine (about 60 minutes), themixture was heated for an additional 2 hours, then excess toluene wasremoved by distillation. After cooling to ambient temperature, theresidue was partitioned between ethyl acetate and saturated aqueousNaHCO₃. After separation of the layers, the ethyl acetate layer waswashed once with brine, dried (MgSO₄) and concentrated to leave anorange gum. Chromatographing the material over silica gel using ethylacetate as the eluent afforded the desired product (0.70 g, 75%) as awhite solid; tlc, R_(f) =0.21, silica gel, ethyl acetate.

EXAMPLE 2 a.9-Amino-2,3-dihydro-5-butyl-2-propylpyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=butyl Rb=propyl, Rc=H)

A mixture of the enamine (1.0 g) described in Example 2g and zincbromide (0.16 g, which had been dried under high vacuum at 180° for 1hour and cooled to ambient temperature) in methylene chloride (5.0 ml)maintained under an argon atmosphere was cooled in an ice bath. To thiswas added dropwise a methylene chloride solution (about 10 ml) offreshly prepared dipropylzinc (about 0.8 g). Following the addition, thereaction mixture was warmed to ambient temperature and stirred for 1hour. The mixture was then heated to reflux with stirring for 24 hours.After cooling to ambient temperature the mixture was quenched by pouringit slowly into excess cold aqueous saturated NH₄ Cl. After stirring for10 minutes, ethyl acetate was added and the layers separated. Theaqueous phase was extracted with additional ethyl acetate and thecombined organic layer was washed with brine, dried over MgSO₄ andconcentrated. The crude product was purified by column chromatographyover silica gel using ethyl acetate:hexane (2:3) as the eluent. Theisolated product was then recrystallized from tertbutylmethyl ether toafford the title compound (0.42 g, 41%) as an off-white crystallinesolid; m.p. 126°-126.5°; tlc, R_(f) =0.40, silica gel, ethylacetate:hexane (1:1).

Analysis calculated for: C₁₈ H₂₄ N₃ O: C, 72.69; H, 7.79; N, 14.13;Found: C, 72.74: H, 7.74; N, 14.13.

b. 3-[2-(Dimethylamino)ethenyl]-2-nitrobenzonitrile

A mixture of 3-methyl-2-nitrobenzonitrile from Example 1c (5.72 g) andtert-butoxy-bis(dimethylamino)methane (9.5 ml) in dimethylformamide (30ml) was heated to 90° with stirring for 1.5 hours. After cooling toambient temperature the mixture was partitioned between ethyl acetateand water. The layers were separated with the aqueous phase furtherextracted using two portions of ethyl acetate. The combined ethylacetate layer was washed with water then brine. The solution was driedover MgSO₄ and filtered through a small pad of silica gel. Afterconcentrating the material a very dark brown solid was obtained.Recrystallization from ethyl acetate/hexane gave the title product (6.99g, 91%) as dark brown crystals.

c. 3-Cyano-2-nitrobenzaldehyde

To a solution of the enamine (1.55 g) prepared in Example 2b intetrahydrofuran:water (35 ml: 7 ml) was added osmium tetroxide (about 30mg). After stirring for 10 minutes, NaIO₄ (1.0 g) was added all at oncemaintaining the reaction temperature at less than 28° by a cool waterbath. Over the next 30 minutes, four portions of NaIO₄ (0.5 g perportion) were added about 6-8 minutes apart. A few minutes after thelast portion of NaIO₄ was added, a final portion (0.21 g) was added fora total of 3.21 g of NaIO₄. The reaction was maintained at a temperatureNaIO₄. The reaction was maintained at a temperature of less than 30°throughout the addition. After stirring for 1.5 hours, ethyl acetate andadditional water were added. The layers were separated and the aqueouslayer was extracted with additional ethyl acetate. The combined ethylacetate layer was washed with brine, dried over Na₂ SO₄ andconcentrated. Chromatographic isolation over silica gel using ethylacetate:hexane (2:3) as the eluent afforded the aldehyde (1.01 g, 80%)as a yellow solid: m.p. 109°-111°; tlc, R_(f) =0.34, silica gel, ethylacetate:hexane (1:1).

d. 3-(Hydroxymethyl)-2-nitrobenzonitrile

To a solution of NaBH₄ (0.2 g) in ethanol (10 ml) at ice bathtemperature was added a solution of 3-cyano-2-nitrobenzaldehyde fromExample 2c (0.93 g) in ethanol:tetrahydrofuran (15 ml:15 ml). After theaddition was completed, the solution was warmed to ambient temperatureand stirred for 30 minutes. The volatiles were removed under aspiratorvacuum and the residue suspended in water. Dilute (1% aqueous)hydrochloric acid was added slowly until gas evolution had ceased. Ethylacetate was then added followed by saturation of the aqueous layer withK₂ CO₃. The layers were separated and the ethyl acetate layer was washedwith brine, dried (Na₂ SO₄) and concentrated to leave the title product(0.85 g, 90%) as a yellow solid; tlc, R_(f) =0.25, silica gel, ethylacetate:hexane (1:1).

e. 2-Amino-3-(hydroxymethyl)benzonitrile (Formula IV, A=formula Ia,Ra=hydroxymethyl)

To a suspension of zinc dust (1.84 g) in tetrahydrofuran (8.0 ml)stirred mechanically at 0° under an argon atmosphere was slowly addedtitanium (III) chloride (10 ml of a 20% (w/w) solution in water). Themixture was stirred vigorously for 30 minutes at ice bath temperature. Asolution of 3-(hydroxymethyl)-2-nitrobenzonitrile from Example 2d (1.0g) in tetrahydrofuran (4.0 ml) was then added over a 2-3 minutes periodto the zinc-titanium (III) chloride mixture. After stirring for 15minutes, aqueous sodium hydroxide (20%) was added to bring the pH of themixture to about 7. Addition of more water and some ethyl acetate wasnecessary to allow efficient stirring. The mixture was filtered througha pad of diatomaceous earth. The pad of diatomaceous earth was mixedwith fresh ethyl acetate after filtration and the suspension wasre-filtered through fresh diatomaceous earth. The combined filtrateswere separated and the separated aqueous phase extracted with freshethyl acetate. The combined ethyl acetate layer was washed with brine,dried (Na.sub. 2 SO₄) and concentrated. The crude product was purifiedby chromatographing it over silica gel using ethyl acetate:hexane (1:1)as the eluent. The title product was obtained (0.71 g, 85%) as a lightyellow solid; m.p. 117°-119.5°; tlc, R_(f) =0.37, silica gel, ethylacetate:hexane (1:1).

f. 2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-(hydroxymethyl)benzonitrile(Formula IIa, A=formula Ia, X=N, n=1, Ra=hydroxymethyl, Rb=propyl)

Using the procedure described in Example 1e, freshly prepared1-propyl-2,4-dioxopyrrolidine was made from3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (21.3 g) in acetonitrile(3500 ml). A mixture of the 1-propyl-2,4-dioxopyrrolidine,2-amino-3-(hydroxymethyl)benzonitrile from Example 2e (9.87 g), andp-toluenesulfonic acid (0.64 g) in toluene:methylene chloride (50 ml:50ml) was heated to gentle reflux. The reaction mixture was surmountedwith a Dean-Stark trap to remove water removed as an azeotrope withmethylene chloride and toluene. Heating was continued until about 50 mlof solvent had been collected. An additional portion of methylenechloride (75 ml) was added and 50 ml was additionally collected. Themixture was cooled to ambient temperature and partitioned between ethylacetate and saturated aqueous NaHCO₃. The layers were separated and theaqueous phase extracted with additional ethyl acetate. The combinedorganic layer was washed with water then brine. After drying (MgSO₄) andconcentrating, the crude product was purified by chromatographing itover silica gel using ethyl acetate:hexane (2:3) as the eluent. Theenamine (17.4 g, 96%) was obtained as a viscous liquid which slowlysolidified upon standing: tlc, R_(f) =0.17, silica gel, ethylacetate:hexane (1:1).

g. 2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-(chloromethyl)benzonitrile(Formula IIa, A'=formula Ia,

X=N, n=1, Ra=--CH₂ Cl, Rb=propyl)

The enamine prepared in Example 2f (6.31 g) was mixed withtriphenylphosphine (6.69 g) and carbon tetrachloride (22.5 ml) inmethylene chloride (50 ml). After stirring overnight (about 15 hours) anadditional portion of triphenylphosphine (1.83 g) was added and themixture stirred for an additional 4 hours. The volatiles were removedand the residue partitioned between ethyl acetate and water. The layerswere separated and the aqueous phase was extracted using additionalethyl acetate. The combined organic layer was washed with brine, driedand concentrated. The residual oil was dissolved in methylenechloride:hexane (1:1, 60 ml) and scratching begun until induction ofcrystallization. After a few hours the desired product was filtered offand the product was washed with methylene chloride:hexane (1:1). Thefiltrate was concentrated and the resulting solid residue (mostlytriphenylphosphine oxide) was recrystallized from tert-butylmethylether. After filtering off the triphenylphosphine oxide the filtrate wasconcentrated, then recrystallized from methylene chloride:hexane (1:1)to obtain an additional crop of the title compound. The title productwas obtained (4.21 g, 62% total yield) as a light yellow crystallinesolid; m.p. 170°-172.5°; tlc, R_(f) =0.12, silica gel, ether.

EXAMPLES 3-6

The process described in Example 2a was repeated to obtain compounds offormula I, wherein A=formula Ia, X=N, n=1, Rb=propyl, Rc=H and whereinRa was varied as listed in Table I. To obtain compounds of formula I asshown in Table I the following diorganozinc reagents were used in placeof dipropyl zinc: Example 3: diethylzinc: Example 4:bis(2-methylpropyl)zinc; Example 5: bis(2-propyl)zinc; and Example 6:diphenylzinc.

                                      TABLE I                                     __________________________________________________________________________    Example                                                                            Ra      Yield                                                                             m.p.   Elemental Analysis                                    __________________________________________________________________________    3    propyl  66% 159-160°**                                                                    Calculated for C.sub.17 H.sub.21 N.sub.3 O:                                   C, 72.06; H, 7.47; N, 14.83                                                   Found: C, 72.08; H, 7.50; N, 14.08                    4    3-methylbutyl                                                                         44% 125-128°**                                                                    Calculated for C.sub.19 H.sub.25 N.sub.3 O:                                   C, 73.29; H, 8.09; 13.49                                                      Found: C, 72.96; H, 8.06; N, 13.34                    5    2-methylpropyl                                                                        35% 154-155°*                                                                     Calculated for C.sub.18 H.sub.23 N.sub.3 O:                                   C, 72.70; H, 7.79; N, 14.13                                                   Found: C, 72.70; H, 7.68; N, 14.10                    6    benzyl  23% 219-220.5°**                                                                  Calculated for C.sub.21 H.sub.21 N.sub.3 O:                                   C, 76.11; H, 6.39; N, 12.68                                                   Found: C, 75.81; H, 6.64; N, 12.22                    __________________________________________________________________________     *Recrystallization solvent was .sub.- tbutylmethyl ether/hexane.              **Recrystallization solvent was .sub.- tbutylmethyl ether.               

EXAMPLE 7 a.9-Amino-2,3-dihydro-5-(2-thienylmethyl)-2-propylpyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=2-thienylmethyl, Rb=propyl, Rc=H)

Sodium hydride (0.17 g, 55% in oil) was washed under argon with freshlydistilled tetrahydrofuran followed by resuspension in tetrahydrofuran(2.0 ml) and cooling in an ice bath. A solution of the enamine (1.20 g)prepared in Example 7b in tetrahydrofuran (5 ml) was then added dropwiseto the rapidly stirred sodium hydride suspension. Following the additionthe mixture was warmed slowly to ambient temperature with stirring untilgas evolution ceased (about 30 minutes). To the stirred mixture wasadded all at once dry cadmium chloride (0.81 g) followed by slow warmingto vigorous reflux. Once the mixture was refluxing, toluene (5.0 ml) wasadded and heating continued until the heating bath (silicone oil)temperature reached 110°. After 2 hours the mixture was cooled toambient temperature and quenched with water. Ethyl acetate was addedfollowed by a few ml of saturated aqueous ethylenediaminetetracetic aciddisodium salt to remove the cadmium salts. The layers were separatedwith the aqueous phase extracted with additional ethyl acetate. Thecombined organic layer was washed once with saturated aqueous NaHCO.sub.3, then brine, followed by drying over Na₂ SO₄. Concentration of thematerial followed by chromatographic purification over silica gel usingethyl acetate:hexane (1:1) as the eluent afforded a yellow-pink solid.Recrystallization from tert-butylmethyl ether/hexane gave the titlequinoline (0.69 g, 57%) as a light yellow solid; m.p. 202°-203.5°; tlc,R_(f) =0.40, silica gel, ethyl acetate:hexane (1:1).

Analysis calculated for: C₁₉ H₁₉ N₃ OS: C, 67.63; H, 5.68; N, 12.45;Found: C, 67.29; H, 5.41; N, 12.36.

b.2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-(2-thienyl)methylbenzonitrile(Formula II, A=formula Ia, X=N, n=1, Ra=2-thienylmethyl Rb=propyl)

To a suspension of the enamine from Example 2 g (1.80 g) at 0° and dryzinc bromide (0.28 g) in methylene chloride (15 ml) was added dropwisebis(2-thienyl)zinc (about 3.5 g) in methylene chloride (10 ml). Afterstirring 1 hour at 0° and 2 hours at ambient temperature, the mixturewas quenched by pouring it slowly into excess cold aqueous saturated NH₄Cl. After stirring several minutes ethyl acetate was added, the layerswere separated and the aqueous layer was extracted with additional ethylacetate. The combined organic layer was washed with brine, dried overNa₂ SO₄ and concentrated. Purification by column chromatography oversilica gel using ethyl acetate:hexane (1:1) as the eluent afforded thetitle compound as a yellow gum, (1.22 g, 58%); tlc, R_(f) =0.36, silicagel, ethyl acetate:hexane (3:1).

EXAMPLES 8-9

The process described in Example 7 was repeated for the synthesis ofcompounds of the formula II where A=formula Ia, Rb=propyl, Rc=H, X=N,n=1, and Ra=cyclopentylmethyl (Example 8) or cyclopropylmethyl (Example9) by substituting the diorganozinc reagents dicyclopentylzinc anddicyclopropylzinc, respectively, for the bis(2-thienyl)zinc in Example7b. The results of these Examples are included in Table II.

                                      TABLE II                                    __________________________________________________________________________                Enamine                                                                            Quinoline                                                    Example                                                                            Ra     Yield                                                                              Yield                                                                              m.p.  Elemental Analysis                                __________________________________________________________________________    8    cyclopentyl-                                                                         99%  48%  160-160.5°                                                                   Calculated for C.sub.20 H.sub.25 N.sub.3 O:            methyl                 C, 74.27; H, 7.79; N, 12.99                                                   Found: C, 73.88; H, 7.75;                                                     N, 12.93                                          9*   cyclopropyl-                                                                         60%  77%  157.5-158°                                                                   Calculated for C.sub.18 H.sub.21 N.sub.3 O:            methyl                 C, 73.19; H, 7.17; N, 14.23                                                   Found: C, 73.24; H, 7.15;                                                     N, 14.16                                          __________________________________________________________________________     *The dicyclopropylzinc used (instead of bis(2thienyl)zinc) was prepared b     a method described in Method. der Organischen Chemie, supra, at page 598.

EXAMPLE 10 a.9-Amino-2,3-dihydro-5-pentyl-2-propylpyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=pentyl, Rb=propyl, Rc=H)

The procedure described in Example 7a was followed except for thefollowing changes or substitutions: the enamine from Example 10f (1.10g) was used instead of the enamine of Example 7b; NaH (0.79 g, 55% inoil instead of 0.17 g), tetrahydrofuran (5.0 ml instead of 2.0 ml),cadmium chloride (0.79 g instead 0.81 g) and toluene (5.0 ml instead ofthe amount indicated in Example 7a). After completion of the reactionand isolation of the crude product as described in Example 7a, theproduct was purified by column chromatography over silica gel usingethyl acetate:hexane (3:7) as the eluent. Recrystallization of theproduct afforded the title compound as a white solid (0.73 g, 66%); m.p.140.5°-142°; tlc, R_(f) =0.38, silica gel, ethyl acetate:hexane (1:1).

Analysis calculated for: C₁₉ H₂₅ N₃ O: C, 73.29; H, 8.09; N, 13.49;Found: C, 73.37; H, 8.06; N, 13.64.

b. N-(Isonitrosoacetyl)-2-pentylaniline

To a warm (about 40°-45°) solution of chloral hydrate (10.1 g) andsodium sulfate decahydrate (108 g) in 400 ml of water was added asolution of 2-pentylaniline hydrochloride (10.3 g) in 400 ml of water.

A solution of hydroxylamine hydrochloride (11.7 g) in water (65 ml) wasnext added and the mixture heated rapidly until an internal temperatureof about 103°-104° was achieved. The mixture was stirred for 15 minutesat this temperature followed by cooling in an ice bath and adding ethylacetate. The layers were separated with the aqueous phase furtherextracted with ethyl acetate. The combined organic phase was washed withbrine, dried over Na₂ SO₄ and concentrated. Purification by columnchromatography over silica gel using ethyl acetate:hexane (1:4) affordedthe title product as a brown oil (9.1 g, 75%); tlc, R_(f) =0.28, silicagel, ethyl acetate:hexane (1:3).

c. 7-Pentylisatin

To warm (about 50°) concentrated sulfuric acid (30 ml) was added inseveral portions the product described in Example 10b (9.1 g). Themixture was rapidly warmed to 80° then stirred for 3-4 minutes. Aftercooling, the mixture was poured with stirring onto ice/water (400 ml).The crude orange solid was extracted with ethyl acetate. The ethylacetate layer was washed with brine, dried over Na₂ SO₄ and then pouredthrough a small pad of silica gel. Recrystallization of the crudeproduct from tert-butylmethyl ether/hexane gave the title product as anorange solid (5.51 g, 66%); m.p. 119°-121°; tlc, R_(f) =0.31, silicagel, ethyl acetate:hexane (1:3).

d. 7-Pentylisatin-3-oxime

A suspension of the isatin described in Example 10c (5.51 g) in ethanol(20 ml) was warmed slightly followed by addition of hydroxylaminehydrochloride (2.47 g) dissolved in water (10 ml). The mixture waswarmed to about 80° with stirring for 10 minutes, followed by cooling toambient temperature and stirring for 30 minutes. The precipitated yellowsolid was filtered off, washed with water and dried to afford the titleproduct (4.50 g, 76%) as a fluffy yellow powder; tlc, R_(f) =0.16,silica gel, ethyl acetate:hexane (2:3).

e. 2-Amino-3-pentylbenzonitrile (Formula IV, Ra=pentyl, A=formula Ia)

Sodium metal (1.11 g) was reacted with methanol (10 ml). The excessmethanol was removed under high vacuum while heating the residue (sodiummethoxide) to 140°. The residue was suspended in diethylene glycol (10ml) followed by addition of the isatin oxime (4.50 g) described inExample 10d. The mixture was heated rapidly to 195° (±10°) for 30minutes. After cooling to ambient temperature, the mixture waspartitioned between ethyl acetate and water. The aqueous phase wasseparated and extracted three times with ethyl acetate:ether (1:1). Thecombined organic layer was dried (MgSO₄) and concentrated to a purpleoil. Purification by column chromatography over silica gel using ethylacetate:hexane (1:9) as the eluent gave the desired compound PG,39 (2.17g, 59%) as a brown oil; tlc, R_(f) =0.60, silica gel, ethylacetate:hexane (1:1).

f. 2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-pentylbenzonitrile (FormulaII, A=formula Ia, X=N, n=1, Ra=pentyl, Rb=propyl)

Freshly prepared 1-propyl-2,4-dioxopyrrolidine generated as described inExample 1e from 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (1.88 g) inacetonitrile (400 ml) was taken up in toluene (3 ml). This solution wasadded dropwise to a refluxing solution of 2-amino-3-pentylbenzonitrile(0.83 g, Example 10e) and p-toluene-sulfonic acid (catalytic) in toluene(5 ml). The toluene/water azeotrope evolved was removed by a Dean-Starktrap. Following the addition of the 1-propyl-2,4-dioxopyrrolidine (about45 minutes) the mixture was heated at reflux for 3 hours. The excesstoluene was distilled off and the residue cooled to ambient temperature.The residue was partitioned between ethyl acetate and saturated aqueousNaHCO₃ and the layers were separated. The aqueous phase was extractedonce with ethyl acetate, then the combined ethyl acetate layer waswashed with brine, dried over Na₂ SO₄ and concentrated to a brown oil.Chromatographic isolation of the material over silica gel using ethylacetate:hexane (3:2) as the eluent afforded the title product as a thickgum (1.12 g, 82%) which slowly solidified upon standing; tlc, R_(f)=0.43, silica gel, ethyl acetate.

EXAMPLE 11 a.9-Amino-5-methyl-2-(2-propenyl)-2,3-dihydrocyclopenta[b]quinolin-1-one(Formula I, A=formula Ia, X=>C-H, n=1, Ra=methyl, Rb=2-propenyl, Rc=H)

The enamine described in Example 11b (1.53 g) was mixed under nitrogenwith copper(I) acetate (1.48 g) in dimethylformamide (17 ml). Themixture was lowered into a pre-heated oil bath at 125° and stirred for3.5 hours. After cooling, the volatiles were removed in vacuo and theresidue partitioned between methylene chloride and aqueous NH₄ OH. Thelayers were separated and the aqueous phase was further extracted withmethylene chloride. The combined methylene chloride layer was filteredto remove some suspended particulate matter. The organic layer was driedover MgSO₄ and concentrated to leave 1.04 g of a brown solid.Chromatography over silica gel using methanol:methylene chloride (3:97)as the eluent gave 0.34 g (22%) of the title compound; m.p. 188.5°-190°;tlc, R_(f) =0.26, silica gel, methanol:methylene chloride (3:97).

Analysis calculated for: C₁₆ H₁₅ N₂ O: C, 76.16; H, 6.39; N, 11.10;Found C, 75.91; H, 6.41; N, 11.00.

b. 2-[1-Oxo-5-(2-propenyl)-2-cyclopenten-3-yl]amino3-methylbenzonitrile(Formula II, A=formula Ia, X=>C-H, n=1, Ra=methyl, Rb=2-propenyl)

The product described in Example 1d (1.55 g) was refluxed together with4-(2-propenyl)-1,3-cyclopentanedione (1.7 g) (prepared as described inU.S. Pat. No. 4,546,104 and p-toluenesulfonic acid (0.25 g) in toluene(36.5 ml). The water evolved was removed as the azeotrope with toluenein a Dean-Stark trap. After heating for 6 hours the volatiles wereremoved in vacuo and the crude residue chromatographed over silica gelusing methanol:methylene chloride (9:191). There was obtained a darkamber powder (1.53 g, 52%) as the title product: tlc, R_(f) =0.26,silica gel, methanol:chloroform (1:24).

EXAMPLE 12 a.9-Amino-5-pentyl-2-(2-propenyl)-2,3-dihydrocyclopenta[b]quinolin-1-one(Formula I, A=formula Ia, X=>C-H, n=1, Ra=pentyl, Rb=2-propenyl, Rc=H)

A procedure similar to that described in Example 7a was followed,however, the following changes and substitutions were made: the enaminedescribed in Example 12b (1.21 g), 0.186 g of sodium hydride, 0.86 g ofanhydrous cadmium chloride in tetrahydrofuran (4 ml instead of 2.0 ml)and toluene (5.0 ml). After work-up and isolation of the crude productas described in Example 7a, the material was chromatographed over silicagel using ethyl acetate:hexane (1:1) as the eluent. Recrystallizationfrom tert-butylmethyl ether/hexane gave the title product (0.71 g, 59%)as a light yellow solid; m.p. 90°-91.5°; tlc, R_(f) =0.58, silica gel,ethyl acetate:hexane (1:1).

Analysis calculated for: C₂₀ H₂₄ N₂ O: C, 77.89; H, 7.84; N, 9.08;Found: C, 77.78; H, 7.95; N, 8.95.

b. 2-[1-Oxo-5-(2-propenyl)-2-cyclopenten-3-yl]amino3-pentylbenzonitrile(Formula II, A=formula Ia, X=>C-H, n=1, Ra=pentyl, Rb=2-propenyl)

A procedure similar to that described in Example 11b was followed usingthe following changes and substitutions: 2-amino-3-pentylbenzonitrile(1.51 g) from Example 10e instead of the nitrile from Example 1d, and4-(2-propenyl)-1,3-cyclopentanedione (1.30 g instead of the amountindicated in Example 11b) in toluene (10 ml instead of the amountindicated in Example 11b). Following a heating interval of 5.5 hours,excess toluene was distilled off and the residue cooled to ambienttemperature. Partitioning of the residue between saturated aqueousNaHCO₃ and ethyl acetate was followed by separation of the layers andwashing of the ethyl acetate layer with brine. After drying andconcentrating the material, the crude product was chromatographed oversilica gel using ethyl acetate:hexane (1:1) as the eluent. There wasobtained the title product (1.21 g, 49%) as a yellow gum; tlc, R_(f)=0.23, silica gel, ethyl acetate:hexane (1:1).

EXAMPLE 13 a.8-Amino-3-pentyl-6-propyl-5,6-dihydrothieno[3,4-e]pyrrolo[3,4-b]pyridin-7(1H)-one(Formula I, A=formula Ib, X=N, Y=S, n=1, Ra=pentyl, Rb=propyl, Rc=H)

The product described in Example 13d (0.73 g) was added to a stainlesssteel bomb to which was also added ethanol (15 ml) which had beenpre-saturated with gaseous ammonia at 0°. The bomb was sealed thenheated to 100° overnight (about 15 hours). After cooling andconcentrating the material, the resulting dark solid was purified bycolumn chromatography over silica gel using ethyl acetate:hexane (1:1)as the eluent. The chromatographed material was recrystallized fromethyl acetate/ether to give a yellow solid (0.50 g, 72%) as the titleproduct; m.p. 167°-169°; tlc, R_(f) =0.20, silica gel, ethylacetate:hexane (1:1).

Analysis calculated for C₁₇ H₂₃ N₃ OS: C, 64.32; H, 7.30; N, 13.24;Found: C, 64.15; H, 7.34; N, 13.10.

b.3-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-2-pentyl-4-carbomethoxythiophene

Freshly prepared 1-propyl-2,4-dioxopyrrolidine was prepared as describedin Example 1e from 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (3.55 g)in acetonitrile (100 ml). The 1-propyl-2,4-dioxopyrrolidine was mixedwith methyl 3-amino-2-pentylthiophene-4-carboxylate (2.70 g) in toluene(65 ml). The mixture was refluxed for 2 hours with removal of thewater/toluene azeotrope using a Dean-Stark trap. After distilling offthe excess toluene, the residue was taken up in ethyl acetate, washedsequentially with saturated aqueous Na₂ CO₃ and brine, then dried (Na₂SO₄) and concentrated. Chromatographic purification over silica gelafforded the title product (3.92 g, 94%) as a yellow oil; tlc, R_(f)=0.12, silica gel, ethyl acetate:hexane (1:1).

5,6-Dihydro-8-hydroxy-3-pentyl-6-propyl-pyrrolo-[3,4-b]thieno[3,4-e]pyridin-7(lH)-one(Formula VII, n=1, X=N, Ra=pentyl, Rb=propyl, W=OH)

A solution of the enamine (1.70 g) described in Example 13b was added toa solution of freshly prepared sodium ethoxide in ethanol (0.11 g ofsodium in 5.0 ml ethanol). An additional 10 ml of ethanol was requiredto assist stirring, then the reaction was stirred for 16 hours atambient temperature. The mixture was poured into water (25 ml) and theresulting precipitate collected to afford the title product (1.2 g, 78%)as a yellow solid; m.p. greater than 285°; tlc, R_(f) =0.05, silica gel,methanol:chloroform (1:19).

d.8-Chloro-3-pentyl-6-propyl-5,6-dihydrothieno[3,4-e]pyrrolo[3,4-b]pyridin-7(1H)-one(Formula III, n=1, X=N, Ra=pentyl, Rb=propyl, Z=C1)

The product described in Example 13c (0.94 g) was suspended in thionylchloride (25 ml) followed by the addition of a few drops ofdimethylformamide. After 30 minutes at ambient temperature excessthionyl chloride was removed under aspirator vacuum. Ether was added tothe residue to give a precipitate. Filtration afforded the title product(0.73 g, 74%) as an orange powder; tlc, R_(f) =0.88, silica gel,methanol:chloroform (1:19).

EXAMPLES 14-15

The process described in Example 13d was repeated using butyl andpropyl-substituted thiophenes made according to the method described inU.S. Pat. No. 4,317,915 to prepare compounds of formula IV whereRa=butyl and propyl and A=formula Ib. These butyl-and propyl-substitutedthiophenes were used for Examples 14 and 15 respectively. Table IIIlists compounds of formula I with A=formula Ib, X=N, n=1, Rb=propyl, andRc=H, and where Ra has a value as shown in the table.

                                      TABLE III                                   __________________________________________________________________________    Example                                                                             Ra   Yield*                                                                             m.p.   Elemental Analysis                                     __________________________________________________________________________    14    butyl                                                                              22%  184-185°**                                                                    Calculated for C.sub.16 H.sub.21 N.sub.3 OS                                   C, 63.33; H, 6.98; N, 13.85                                                   Found: C, 63.37; H, 7.02; N, 13.68                     15    propyl                                                                             26%  200-202°***                                                                   Calculated for C.sub.15 H.sub.19 N.sub.3 OS                                   C, 62.25; H, 6.62; N, 14.52                                                   Found: C, 61.66; H, 6.58; N, 14.28                     __________________________________________________________________________     *Yield is for last step.                                                      **Recrystallized from .sub.- tbutylmethyl ether/hexane/ethyl acetate.         ***Recrystallized from ethyl acetate/hexane.                             

EXAMPLE 16 a.8-Amino-5,6-dihydro-3-pentyl-6-propyldipyrrolo[3,2-b:3,4-e]pyridin-7(1H)-one(Formula I, A=formula Ic, X=N, Y=>N=Rd, n=1, Ra=pentyl, Rb=propyl, Rc=H,Rd=H)

A procedure similar to that described in Example 7a was followed usingthe enamine prepared in Example 16e (1.65 g) instead of the enamine fromExample 7b, sodium hydride (0.25 g, 55% in oil instead of 0.17 g) andcadmium chloride (1.05 g) in toluene (20 ml) with the same amount oftetrahydrofuran (2 ml) as used in Example 7a. A small amount ofdimethylformamide was also present to help solubilize the enamine at thebeginning of the reaction. Following the heating interval (1.5 hours at110°) the mixture was cooled to ambient temperature and concentrated invacuo. The residue was partitioned using water and ethylacetate:tetrahydrofuran (2:1) with a little ethylenediaminetetraaceticacid (EDTA) added. The layers were separated and the aqueous phase wasextracted with additional ethyl acetate. The combined organic layer waswashed with brine, dried (MgSO₄) and concentrated. The crude product waschromatographed over silica gel using methanol:methylene chloride (1:19)as the eluent. The resulting solid was recrystallized fromtetrahydrofuran/ethyl acetate/methanol to leave the title product as awhite solid (1.01 g, 61%); m.p. greater than 225°; tlc, R_(f) =0.13,silica gel, methanol:chloroform (1:19).

Analysis calculated for C₁₇ H₂₄ N₄ O: C, 67.96; H, 8.05; N, 18.65;Found: C, 67.60; H, 7.92; N, 18.18.

b. 2-Formylheptanonitrile

A solution of potassium tert-butoxide (18.9 g) in a mixed solvent systemof tetrahydrofuran (150 ml) and toluene (100 ml) was heated to 75°. Asolution of heptanonitrile (11.2 g) and ethyl formate (24 ml) in toluene(50 ml) was then added dropwise to the warm tert-butoxide solution. Thereaction was stirred for 5 hours at 75° then cooled with an ice bath.Ether was added to the mixture and then water. The layers wereseparated. The aqueous phase was washed once with ether then acidifiedto a pH of about 3 with aqueous hydrochloric acid (6N). The aqueousphase was saturated with sodium chloride then extracted twice withether. The combined ether extracts were washed with brine, dried (MgSO₄)and concentrated to leave the title product as a yellow oil (10.7 g,77%).

c. 2-[(Cyanomethyl)aminomethylene]heptanonitrile

2-Formylheptanonitrile (10.7 g), sodium acetate (7.9 g) andaminoacetonitrile hydrochloride (8.9 g) were mixed together in 200 ml ofmethanol:water (8:2). After stirring for 2 hours at ambient temperaturethe methanol was removed under aspirator vacuum and the residuepartitioned between ethyl acetate and water. The layers were separatedand the ethyl acetate layer was washed with brine, dried (Na₂ SO₄) andconcentrated to leave a yellow oil. Chromatographic purification of thematerial over silica gel using ethyl acetate/hexane as the eluentafforded a light yellow solid as a mixture of isomers (11.6 g, 85%);tlc, R_(f) =0.37 and 0.50 silica gel, ethyl acetate:hexane (1:1).

d. 3-Amino-2-cyano-4-pentylpyrrole (Formula IV, A=formula Ic, Y=>N-Rd,Ra=pentyl, Rd=H)

To a solution at 0° of the product described in Example 16c (11.1 g) andtriethylamine (10.4 ml) in methylene chloride (100 ml) was addeddropwise ethyl chloroformate (6.90 ml). The resulting dark mixture wasstirred for one hour at 0° followed by warming to ambient temperatureand adding 1,8-diazabicyclo[5.4.0]undec-7-ene (11.2 ml). The mixture waswarmed to reflux and stirred for 6 hours. The mixture was then cooled toambient temperature and stirred overnight (about 16 hours). The mixturewas partitioned between ether and water and the layers separated. Theaqueous phase was further extracted with ethyl acetate and the combinedorganic layer was washed with brine, dried (MgSO₄) and concentrated toleave a dark oil. This oil was stirred with anhydrous powdered Na₂ CO₃(1 g) in methanol at ambient temperature for one hour. The volatileswere removed and the residue partitioned between ether and water. Thelayers were separated and the aqueous phase extracted three times withether. The combined ether layer was washed with brine, dried (MgSO₄) andconcentrated. The crude product was chromatographed over silica gelusing ethyl acetate: hexane (1:4) as the eluent. The resulting orangesolid was recrystallized from toluene/hexane to give the title productas an off-white powder (6.05 g, 54%); m.p. 49°-50.5°; tlc, R_(f) =0.26,silica gel, ethyl acetate:hexane (1:3).

e. 3-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-4-pentyl-2-cyanopyrrole(Formula II, A=formula Ic, X=N, Y=>N-Rd, n=1, Ra=pentyl, Rb=propyl,Rd=H)

Fresh 1-propyl-2,4-dioxopyrrolidine was prepared as described in Example1e from 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (1.91 g) inacetonitrile (400 ml). The 1-propyl-2,4-dioxopyrrolidine was thencondensed with 3-amino-2-cyano-4-pentylpyrrole (1.15 g) from Example 16din toluene (20 ml) using a catalytic amount of p-toluenesulfonic acid.After heating at reflux for one hour using a Dean-Stark trap to removethe water evolved, the mixture was cooled to ambient temperature. Theprecipitated solid was filtered off and washed with ether to leave thetitle product as a white solid (1.78 g, 92%); tlc, R_(f) =0.08, silicagel, methanol:chloroform (1:19).

Example 17 a.8-Amino-3-pentyl-6-(2-propenyl)-4,5,6,7-tetrahydropyrrolo[3,2-b]quinolin-7-(1H)-one(Formula I, A=formula Ic, X=>C-H, Y=N-Rd, n=2, Ra=pentyl, Rb=2-propenyl,Rc=H, Rd=H)

The enamine described in Example 17b (3.41 g) was cyclized according tothe procedure described in Example 7a using sodium hydride (0.51 g, 55%in mineral oil instead of 0.17 g) and cadmium chloride (2.11 g insteadof 0.81 g) in tetrahydrofuran (10.0 ml instead of 2.0 ml) and toluene(10.0 ml instead of the amount indicated in Example 7a). The reactionrequired 15 hours at 90°-95° to go to completion after which isolationof the crude product was accomplished as described in Example 7a. Thecrude material was chromatographed over silica gel using ethyl acetate:hexane (1:1) as the eluent to obtain the title product (2.66 g, 78%) asa white solid; m.p. decomposes at greater than 195°: tlc, R_(f) =0.29,silica gel, ethyl acetate:hexane (1:1) plus about 2% triethylamine.

Analysis calculated for: C₁₉ H₂₅ N₃ O: C, 73.19; H, 8.09; N, 13.49;Found: C, 72.58: H, 8.04; N, 13.21 .

b.3-[1-Oxo-5-(2-propenyl)-2-cyclohexen-3-yl)amino-4-pentyl-2-cyanopyrrole(Formula II, A=formula

Ic, X=>C-H, Y=>N-Rd, n=2, Ra=pentyl, Rb=2-propenyl, Rc=H, Rd=H)

A mixture of 3-amino-2-cyano-4-pentylpyrrole (2.0 g) from Example 16dand 4-(2-propenyl)-1,3-cyclohexanedione (2.06 g, prepared as describedin U.S. Pat. No. 4,546,104) was heated in toluene (25 ml) containing acatalytic amount of p-toluenesulfonic acid. The mixture was refluxed for1.5 hours with removal of evolved water as the azeotrope with tolueneusing a Dean-Stark trap. After distilling off excess toluene and coolingto ambient temperature, the residue was partitioned between ethylacetate and saturated aqueous NaHCO₃. The layers were separated. Theethyl acetate layer was washed with brine, dried (MgSO₄) andconcentrated to a thick gum. Chromatographic purification of thematerial over silica gel using ethyl acetate:hexane as the eluent (2:3)afforded the title product (3.41 g, 97%): tlc, R_(f) =0.27, ethylacetate: hexane (1:1).

EXAMPLE 18 a.8-Amino-4,5-dihydro-3-pentyl-1H-6-(2-propenyl)pyrrolo[3,2-b][1,6]napthyridin-7(6H)-one(Formula I, A= formula Ic, X=N, Y=>,N-Rd, n=2, Ra=pentyl, Rb=2-propenyl,Rd=H)

The procedure of Example 17a was followed using the enamine of Example18e (0.71 g) instead of the enamine of Example 17b to obtain 0.30 g(46%) of the title compound as a yellow solid. Addition to ethereal HClgave the hydrochloride salt which was recrystallized from ethanol.

Analysis calculated for: C₁₈ H₂₄ N₄ O.HCl.1/2H₂ O: C, 60.41 H, 7.32; N,15.65; Found: C, 60.14: H, 7.96; N, 15.28.

b. 4-Ethoxy-1,2,5,6-tetrahydro-1H-2-pyridone

A solution of 2,4-dioxopiperidine (2.0 g) in ethanol (45 ml) was heatedto reflux in the presence of a catalytic amount of p-toluenesulfonicacid. After 5 hours at reflux the ethanol was removed and the residuetriturated with tetrahydrofuran to give the title product as a brownsolid (2.48 g); tlc, R_(f) =0.33, silica gel, methanol:chloroform(1:19).

c. 4-Ethoxy-1-(2-propenyl)-1,2,5,6-tetrahydro-2-pyridone

To a suspension of sodium hydride (0.85 g, 55% in mineral oil,pre-washed with tetrahydrofuran) in tetrahydrofuran (30 ml) maintainedat ice bath temperature was slowly added the product from Example 18b(2.48 g). After 20 minutes 1-bromo-2-propene (1.52 ml) was slowly added.The mixture was warmed to ambient temperature and stirred for 48 hours.The mixture was diluted with water then extracted with ethyl acetate.After drying (MgSO₄ 0 and concentrating the material, the residue waschromatographed over silica gel using methanol:chloroform (1:19) as theeluent. There was obtained 1.0 g (31%) of product; tlc, R_(f) =0.62,silica gel, methanol:chloroform (1:19).

d. 1-(2-Propenyl)-2,4-dioxopiperidine (Formula V, X=N, n=2,Rb=2-propenyl)

A solution of the product described in Example 18c (1.5 g) intetrahydrofuran (10 ml) and aqueous hydrochloric acid (10 ml of 10%) wasstirred at ambient temperature for about 15 hours. Sodium chloride wasthen added to saturate the aqueous phase and the mixture was extractedwith several portions of ethyl acetate. The combined extracts were dried(MgSO₄) and concentrated to leave the title product as a clear oil (1.0g, 79%): tlc, R_(f) =about 0.05, silica gel, methanol:chloroform (1:19).

e. 3-[1-(2-Propenyl)-2,4-dioxopiperidyl]-amino-4-pentyl-2-cyanopyrrole(Formula II, A=formula Ic' X=N, Y=>N-Rd, n=2, Ra=pentyl, Rb=2-propenyl,Rd=H)

The process described in Example 17b was repeated using1-(2-propenyl)-2,4-dioxopiperidine (1.0 g) and3-amino-2-cyano-4-pentylpyrrole (0.53 g) to give 0.71 g (76%) of thetitle enamine.

EXAMPLE 19 a.4-Amino-6,7-dihydro-1-pentyl-6-propyldipyrrolo-[2,3-b:3,4-e]pyridin-5(1H)-one(Formula I, A=formula ula Id, X=N, n=1, Ra=pentyl, Rb=propyl, Rc=H)

The enamine prepared in Example 19c (0.75 g) was cyclized according tothe procedure of Example 7a using sodium hydride (0.12 g, 55% in mineraloil instead of 0.17 g) and cadmium chloride (0.55 g instead of 0.81 g)in tetrahydrofuran (2 ml, the same amount as in Example 7a) and toluene(2 ml instead of the amount indicated in Example 7a) to give, afterisolation of the crude product as described in Example 7a, a brownsolid. The crude product was chromatographed over silica gel usingmethanol:methylene chloride (4:1) as the eluent. The solid obtained wasrecrystallized from tert-butylmethyl ether/hexane to give the titlecompound as a white solid (0.52 g, 69%); m.p. 138°-138.5° ; tlc, R_(f)=0.30, silica gel, methanol: chloroform (1:19).

Analysis calculated for: C₁₇ H₁₂₄ N₄ O: C, 67.97; H, 8.05; N, 18.65;Found: C, 68.18; H, 8.36: N, 17.

b. 2-Amino-3-cyano-1-pentylpyrrole (Formula IV, A=formula Id, Ra=pentyl)

To a solution of 1-carboethoxy-2-amino-3-cyanopyrrole (1.55 g, preparedaccording to the procedure described in Chem. Pharm. Bull; Vol. 30,2357-2363 (1982)) in dry methanol (15 ml) was added K₂ CO₃ (0.60 g).After 30 minutes at ambient temperature the methanol was removed invacuo and the dark residue was taken up in dimethylformamide (15 ml).This solution was added to a suspension of sodium hydride (0.45 g, 55%in mineral oil, pre-washed with dry tetrahydrofuran) at 0° indimethylformamide (5 ml). The mixture was warmed to ambient temperaturewith stirring for 10 minutes followed by the addition of 1-bromopentane(1.61 ml). The reaction was stirred for 15 minutes then poured intowater and extracted with ethyl acetate. The ethyl acetate extracts werewashed with water and then brine. The material was dried (MgSO₁₄) andconcentrated. The residue was chromatographed over silica gel, elutingwith methanol:methylene chloride (1:49) to give the title product as alight brown oil (0.66 g, 43%): tlc, R_(f) =0.46, silica gel,methanol:chloroform (1:49).

c. 2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-cyano-1-pentylpyrrole(Formula II, A=formula Id, X=N, n=1, Ra=pentyl, Rb=propyl)

Fresh 1-propyl-2,4-dioxopyrrolidine was prepared as described in Example1e from 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (1.01 g) inacetonitrile-(100 ml). A mixture of the 1-propyl-2,4-dioxopyrrolidineand 2-amino-3-cyano-1-pentylpyrrole (0.60 g) from Example 19b was heatedin toluene (10 ml) along with a catalytic amount of p-toluenesulfonicacid. The mixture was refluxed for one hour with removal of thetoluene/water azeotrope in a Dean-Stark trap. After concentrating thematerial, the residue was partitioned between ethyl acetate and water;the layers were separated and the ethyl acetate layer was dried

After filtration and concentration the over MgSO₄. After filtraton andconcentration the residue was chromatographed over silica gel usingmethanol:methylene chloride (3:1) to give the title purple solid (0.95g, 94%); tlc, R_(f) =0.34, silica gel, methanol:methylene chloride(3:1).

EXAMPLE 20 a.4-Amino-6,7-dihydro-1-butyl-6-propyldipyrrolo-[2,3-b:3,4-e]pyridin-5(1H)-one(Formula I, A=formula Id, X=N, n=1, Ra=butyl, Rb=propyl, Rc=H)

The process of Example 19a was repeated using the enamine of Example 20c(1.05 g), sodium hydride (0.18 g, 55% in mineral oil), and cadmiumchloride (0.18 g) instead of the amounts and enamine used in Example19a. Cyclization of the enamine gave the title compound (0.73 g, 69%):m.p. 169°-171°; tlc, R_(f) =0.24, silica gel, ethyl acetate:hexane(1:1).

Analysis calculated for: C₁₆ H₂₂ N₄ O: C, 67.11: H, 7.74; N, 19.56;Found: C, 66.96; H, 8.00; N, 19.06.

b. 2-Amino-3-cyano-1-butylpyrrole (Formula IV, A=formula Id, Ra=butyl)

The process described in Example 19b was repeated using 1.45 g of the1-carboethoxy-2-amino-3-cyanopyrrole and 1-iodobutane (1.01 ml) toprepare the title compound (0.77 g, 58%).

c. 2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-cyano-1-butylpyrrole(Formula II, A=formula Id, X=N, n=1, Ra=butyl, Rb=propyl)

The process of Example 19b was repeated using the butylpyrrole ofExample 19b to make the title enamine compound (1.05 g, 78%).

EXAMPLES 21-25

The process in Example 7 was repeated for the synthesis of compounds offormula II where A=formula Ia, Rb=propyl, Rc=H, X=N, n=1 and Ra isselected from 2-methylbutyl (Example 21): cyclohexylmethyl (Example 22):2,2-dimethylpropyl (Example 23): 2-phenylethyl (Example 24); and(3-thienyl)methyl (Example 25) by substituting the appropriatediorganozinc reagents for bis(2-thienyl)zinc in Example 7b. Theresulting enamines were then cyclized according to the process describedin Example 7a to afford compounds of the formula I as listed in TableIV.

                                      TABLE IV                                    __________________________________________________________________________                   Enamine                                                                            Quinoline                                                                          Quinoline                                            Example                                                                            Ra        Yield                                                                              Yield                                                                              m.p.  Elemental Analysis for Quinoline               __________________________________________________________________________    21   2-methylbutyl                                                                           95%  58%* 138-139.5°                                                                   Calculated for C.sub.19 H.sub.25 N.sub.3                                      O: C, 73.28; H, 8.04;                                                         N, 13.49                                                                      Found: C, 73.53; H, 7.70; N, 13.46             22   cyclohexylmethyl                                                                        83%  57%**                                                                              186.5-187.5°                                                                 Calculated for C.sub.21 H.sub.27 N.sub.3                                      O: C, 74.74; H, 8.06;                                                         N, 12.45                                                                      Found: C, 74.58; H, 8.00; N, 12.30             23   2,2-dimethylpropyl                                                                      89%  52%* 175-177°                                                                     Calculated for C.sub.19 H.sub.25 N.sub.3                                      O: C, 73.28; H, 8.09;                                                         N, 13.49                                                                      Found: C, 73.27; H, 8.10; N, 13.46             24   2-phenylethyl                                                                           84%  76%***                                                                             187-190°                                                                     Calculated for C.sub.22 H.sub.23 N.sub.3                                      O: C, 76.49; H, 12.16;                                                        N, 6.71                                                                       Found: C, 76.12; H, 12.05; N, 6.64             25   3-thienylmethyl                                                                         78%  39%***                                                                             210-211°                                                                     Calculated for C.sub.19 H.sub.19 N.sub.3                                      O.S: C, 67.63; H, 5.68                                                        N, 12.45                                                                      Found: C, 66.86; H, 5.62; N,                   __________________________________________________________________________                                   12.22                                           *Recrystallized from tertbutylmethyl ether/hexane                             **Recrystallized from tertbutylmethyl ether/ethyl acetate                     ***Recrystallized from ethyl acetate                                     

EXAMPLE 26 a. 9-Amino-2-benzyl-2,3-dihydro-5-(2-methylpropyl)pyrrolo[3,4-b]quinolin-1-one (Formula I, A=formula Ia, X=N, n=1,Ra=2-methylpropyl, Rb=benzyl, Rc=H)

The enamine from Example 26f plus an additional sample prepared asdescribed in Examples 26 b-f (1.15 g) were reacted with sodium hydride(0.172 g, 55% in oil) in tetrahydrofuran as described in Example 7a.After warming to ambient temperature the cadmium chloride (7.63 g) wasadded and the mixture heated to reflux. A few milliliters (ml) oftoluene were added and the heating continued (bath temperature=100° )for 40 minutes. After cooling to ambient temperature, saturated aqueousdisodium ethylenediaminetetraacetic acid was added and the productworked up as described in Example 7a. The crude product was purified bycolumn chromatography using ethyl acetate:methylene chloride (1:4) asthe eluent. Recrystallization of the product in ethyl acetate affordedthe product as a white solid (1.11 g, 96%); m.p., 167-170° ; tlc, R_(f)=0.55, silica gel, ethyl acetate:hexane (1:1).

Analysis calculated for: C₂₂ H₂₃ N₃ O: C, 76.49; H, 6.71: N. 12.16;Found: C, 76.35; H, 6.68; N, 12.08.

b. Ethyl N-(ethoxycarbonylacetyl)-N-benzylglycinate

To a 0° C solution of ethyl N-benzylglycinate (8 g) in tetrahydrofuran(4 ml) and diethyl ether (42 ml) was added simultaneously a solution ofK₂ CO₃ (5.72 g) in 20 ml of water and ethyl malonylchloride (6.54 g) in20 ml diethyl ether. Following the addition the mixture was stirred at0° for 1 hour then warmed to ambient temperature with stirring for 2hours. The layers were separated with the organic phase washed once withbrine. After drying (Na₂ SO₄) and concentrating, there was obtained 12.5g (98.8%) of the product as a viscous oil.

c. 1-Benzyl-3-carboethoxy-2,4-pyrrolidione

The product from Example 26b (2.0 g) was dissolved in 13 ml of toluene.This solution was added dropwise over a 2 hour period to 6.4 ml of a 1Msolution of sodium chloride in ethanol maintained at ambienttemperature. Following the addition, the mixture was heated to refluxfor 4.5 hours then cooled to ambient temperature. Water (10 ml) wasadded and the layers separated. The organic phase was washed with water(4×30 ml) and the aqueous phases were combined. The aqueous layer wasacidified by adding 6N HCl (aqueous) to bring the pH to approximately 1.The resulting white precipitate was extracted with 3×50 ml of methylenechloride. After drying over Na₂ SO₄, the volatiles were removed to leave1.37 g (81%) of the product as a white solid.

d. 2-(1-Benzyl-2-oxo-3-pyrrolin-4-yl)amino-3-(hydroxymethyl)benzonitrile(Formula II, A=formula Ia, X=N, n=1, Ra=CH20H, Rb=benzyl)

The product described in Example 26c (0.75 g) was decarboethoxylated byboiling in acetonitrile (100 ml) as described in Example 1e for1-propyl-2,4dioxopyrrolidine. The freshly prepared1-benzyl-2,4-dioxopyrrolidine was reacted with 0.35 g of2-amino-3-(hydroxymethyl)benzonitrile (Example 2e) according to theprocedure described in Example 2f. Following isolation of the product asdescribed in Example 2f there was obtained 0.8 g (quantitative) of agummy oil: tlc, R_(f) =0.13: silica gel, ethyl acetate:hexane (3:2).

e. 2-(1-Benzyl-2-oxo-3-pyrrolin-4-yl)amino-3-(chloromethyl)benzonitrile(Formula IIa, A'=formula Ia, X=N, n=1, Ra=CH₂ Cl, Rb=benzyl)

The product obtained in Example 26d (0.8 g) was reacted withtriphenylphosphine (0.72 g) and CCl₄ (2.41 ml) in 25 ml of methylenechloride according to the procedure of Example 2g. After 20 hours anadditional portion of triphenylphosphine was added (0.13 g) and stirringwas continued for 7 hours. The crude product was then isolated asdescribed in Example 2g, then crystallized from methylenechloride:hexane (1:1) to afford 0.400 g (48%) of product: tlc, R_(f)=0.08, silica gel, ethyl acetate:hexane (1:1).

f.2-(1-Benzyl-2-oxo-3-pyrrolin-4-yl)amino-3-(2-methylpropyl)benzonitrile(Formula II, A=formula Ia, X=N, n=1, Ra=2-methylpropyl, Rb=benzyl)

To a 0° suspension of the enamine from Example 26e (0.39 g) and dry zincbromide (0.078 g) in methylene chloride (5 ml) was added dropwisebis(2-propyl)zinc (about 0.52 g) in methylene chloride (3 ml). Afterstirring 1 hour at 0° and 2 hours at ambient temperature, the mixturewas quenched by pouring it slowly into excess cold aqueous saturated NH₄Cl. Ethyl acetate was added, the layers were separated and the aqueouslayer was extracted with additional ethyl acetate. The combined organiclayer was washed with brine, dried over Na₂ SO₄ and concentrated.Purification by trituration with diethyl ether gave 0.40 g (95%) of alight yellow solid.

EXAMPLES 27-28

The process described in Example 26 was repeated for the synthesis ofcompounds of the formula I where A=formula Ia, Ra=2-methylpropyl, Rc=H,X=N, n=1, and Rb is selected from 2-propenyl (Example 27) and2,4-dimethoxybenzyl (Example 28) by substituting ethylN-(2-propenyl)glycinate and ethyl N-(2,4-dimethoxybenzyl)glycinate,respectively, for the ethyl N-benzylglycinate used in Example 26b. TheExamples are listed in Table V.

                                      TABLE V                                     __________________________________________________________________________                   Quinoline                                                      Example                                                                            Ra        Yield                                                                              m.p. Elemental Analysis                                   __________________________________________________________________________    27   2-propenyl                                                                              83%  165-166°*                                                                   Calculated for                                                                C.sub.18 H.sub.21 N.sub.3 O: C, 73.19; H, 7.17;                               N, 14.23                                                                      Found: C, 73.57; H, 6.91; N, 14.24                   28   2,4-dimethoxybenzyl                                                                     64%  194-195°*                                                                   Calculated for                                                                C.sub.24 H.sub.27 N.sub.3 O.sub.3 : C, 71.09; H,                              6.71; N, 10.36                                                                Found: C, 70.75; H, 6.67; N, 10.20                   __________________________________________________________________________     *Recrystallized for tertbutylmethyl ether/hexane                         

EXAMPLE 2910-Amino-6-(2-methylpropyl)-2-propenyl)-1,2,3,4-tetrahydropyrido[4,5-b]quinolin-1(1H)-one(Formula I, A=formula Ia, X=N, n=2,

Ra=2-methylpropyl, Rb=2-propenyl, Rc=H)

The enamine described in Example 29d (1.20 g) was added as a solution intetrahydrofuran (3 ml) to a suspension of freshly washed sodium hydride(0.19 g, 55% in oil) in tetrahydrofuran (5 ml) at 0° C. Following theaddition the mixture was warmed to ambient temperature with stirring onehour. Dry cadmium chloride (0.85 g) was added all at once and themixture slowly warmed to 90°. At this point 5 ml of toluene was addedand the mixture refluxed for 2 hours. After cooling to ambienttemperature, the mixture was quenched by slowly adding excess saturatedaqueous disodium ethylenediaminetetraacetic acid. After stirring severalminutes the product was extracted into ethyl acetate. The ethyl acetatelayer was dried (Na₂ SO₄) and concentrated to leave a dark solid. Thematerial was purified by silica gel column chromatography using ethylacetate:hexane (1:1) as the eluent. The yellow solid was recrystallizedfrom tert-butylmethyl ether/hexane to afford 0.45 g (38%) 1 of paleyellow crystals: m.p. 141°-142° ; tlc, R_(f) 32 0.58, silica gel, ethylacetate.

b.3-[1-(2-Propenyl)-2,4-dioxopiperidyl]amino-3-(hydroxymethyl)benzonitrile(Formula II, A=formula Ia, X=N, n=2, Ra=CH₂₀ H, Rb=2-propenyl)

The product from Example 18d (2.57 g) was heated together with theproduct described in Example 2e (2.37 g) in a solvent mixture consistingof methylene chloride (15 ml) and toluene (15 ml) containing 0.09 g ofp-toluenesulfonic acid. The water/toluene/methylene chloride azeotropewas removed continuously by a Dean-Stark trap. After reaching a bathtemperature of 135° at which point the volatiles had been removed, themixture was cooled to ambient temperature. The residue was partitionedbetween ethyl acetate and saturated aqueous NaHCO₃. The ethyl acetatelayer was separated, washed with brine and dried over MgSO₄. Afterconcentrating, the crude product was purified by column chromatographyover silica gel using ethyl acetate:hexane (1:1) as the eluent. Therewas obtained 4.71 g (quantitative) tlc, R_(f) f=0.18, silica gel, ethylof a yellow oil; acetate:hexane (1:1).

c.3[1-(2-Propenyl)-2,4-dioxopiperid-4-yl)amino-3-(chloromethyl)benzonitrile(FormulaIIa, A'=formula Ia, X=N, n=2, Rb=2-propenyl, Ra=chloro-methyl)

The product from Example 29b (4.53 g) was stirred withtriphenylphosphine (4.82 g) and CCl₄ (15.5 ml) in methylene chloride (50ml) at ambient temperature. After stirring 8 hours an additional portionof triphenylphosphine (1.45 g) was added and stirring was continued for12 additional hours. The volatiles were removed and the residuepartitioned between ethyl acetate and water. The ethyl acetate layer wasdried (Na₂ SO₄) and concentrated to leave a dark brown gum.Crystallization from methylene chloride:hexane (2:3) afforded theproduct (2.97 g, 62%) as an offwhite solid; tlc, R_(f) =0.30, silicagel, methanol: chloroform (1:19).

d.3-[1-(2-Propenyl)-2,4-dioxopiperid-4-yl]-amino-3-(2-methylpropyl)benzonitrile(Formula II,

A=formula Ia, X=N, n=1, Ra=2-methylpropyl,

Rb=2-propenyl)

To a 0° suspension of the enamine from Example 29c (1.2 g) and dry zincbromide (0.27g) in methylene chloride (10 ml) was added dropwisebis(2-propyl)zinc (about 1.8 g) in methylene chloride (5 ml). Afterstirring for 1 hour at 0° and 1 hour at ambient temperature, the mixturewas quenched by pouring it slowly into excess cold aqueous saturated NH₄Cl. Ethyl acetate was added, the layers separated and the organic phasedried over MgSO₄. After concentration, the crude product was purified bycolumn chromatography over silica gel using ethylacetate/tetrahydrofuran as the eluent. There was obtained 1.25 g(quantitative) of product; tlc, R_(f) =0.38, silica gel, ethyl acetate.

EXAMPLE 30 a.10-Amino-6-(2-methylbutyl)-2-(2-propenyl)-1,2,3,4-tetrahydropyrido[4,5-b]quinolin-1-(H)-one(Formula I, A=formula Ia, X=N, n=2, Ra=2-methylbutyl, Rb=2-propenyl,Rc=H)

The enamine described in Example 30b (0.70 g) was reacted with sodiumhydride (0.19 g, 55% in oil) and cadmium chloride (0.88 g) according tothe procedure of Example 29a. After heating at reflux for 1 hour, thereaction was cooled to ambient temperature and excess disodiumethylenediaminetetraacetic acid added as an aqueous solution. Afterstirring for 15 minutes, the product was extracted into ethyl acetate.The extracts were dried (MgSO₄) and concentrated. The crude product waspurified by column chromatography over silica gel using ethylacetate:hexane (1:1) as the eluent. The solid obtained wasrecrystallized from tert-butylmethyl ether/hexane to afford 0.70 g (54%)of the quinoline as white needles; tlc, R_(f) =0.73, silica gel, ethylacetate; m.p. 118°-119°.

Analysis calculated for: C₂₀ H₂₅ N₃ O: C, 74.27; H, 7.79; N, 12.99;Found: C, 74.29: H, 7.80; N, 12.95.

b.3-[1-(2-Propenyl)-2,4-dioxopiperid-4-yl)amino-3-(2-methylbutyl)benzonitrile(Formula II, A=formula Ia, X=N, n=1, Ra=2-methylbutyl, Rb=2-propenyl)

The product from Example 29c (1.30 g) was reacted with bis(2-butyl)zinc(2.13 g) and zinc bromide (0.29 g) in 10 ml of methylene chloride,according to the procedure of Example 29d. After stirring for 1 hour at0° and 1 hour at ambient temperature, the crude product was isolated asdescribed in Example 29d. There was obtained 1.6 g of a beige solid(quantitative); tlc, R_(f) =0.38, silica gel, ethyl acetate.

EXAMPLE 31 a.9-Amino-2,3-dihydro-5-(3-trifluoromethylbutyl)-2-propylpyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=3-trifluoromethylbutyl,Rb=propyl, Rc=H)

To a suspension of magnesium turnings (0.55 g) in diethyl ether (2 ml)at ambient temperature was added dropwise3-trifluoromethyl-1-bromobutane (3.90 g). A little gentle warming wasnecessary to help initiate Grignard reagent formation. After theaddition was complete the mixture was refluxed for 1 hour to ensurecomplete formation of the reagent. After cooling to ambient temperaturethe Grignard reagent was added slowly to a solution of zinc bromide (4.5g) in tetrahydrofuran (10 ml). The thick, white mixture was stirred 2hours at ambient temperature followed by addition ofdichloro-[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (0.16 g)and stirring for an additional 5 minutes. The bromoquinoline describedin Example 31 g (1.20 g) was next added and the mixture heated to refluxfor 10 hours. After cooling to ambient temperature a few milliliters ofsaturated NH₄ Cl (aqueous) was added followed by partitioning themixture between aqueous disodium ethylenediaminetetraacetic acid andethyl acetate. After stirring for 30 minutes, the layers were separated.The organic phase was washed with brine, dried (Na₂ SO₄) andconcentrated. The crude product was 10 purified by column chromatographyover silica gel using ethyl acetate:hexane (1:3) as the eluent.Recrystallization of the purified material from tert-butylmethylether/hexane afford 0.13 g (8.7%) of the desired product: tlc, R_(f)=0.40, silica gel, ethyl acetate:hexane (1:1); m.p., 118-120.

Analysis calculated for: C₁₉ H₂₂ N₃ OF₃ : C, 62.46; H, 6.07: N, 11.50;Found: C, 62.21; H, 6.03: N, 11.43.

2-Bromoisonitrosoacetanilide

To a warm (40°) solution containing 1.51 Kg Na₂ SO₄.10H₂ O and chloralhydrate (84.0 g) in 1 liter of water was added all at once a solution of2-bromoaniline (80.5 g) in 160 ml of water also containing 40 ml ofconcentrated HCl. To this mixture was added hydroxylamine hydrochloride(100.8 g) in 200 ml of water. The mixture was heated to reflux withmonitoring of the internal reaction temperature. After 40 minutes at104° the reaction was cooled to ambient temperature and extracted withethyl acetate. The extracts were dried (MgSO₄) and concentrated to leavea dark brown solid. The solid was triturated with methylenechloride/hexane to leave 80 g (69%) of 1 a light brown solid: tlc, R_(f)=0.57, silica gel, ethyl acetate:hexane (2:3).

c. 7-Bromoisatin

To 250 ml of warm (about 50°) concentrated sulfuric acid was added theproduct described in Example 31b (80 g) in several portions. Theinternal temperature was maintained below 65° during the addition. Aftercomplete addition the reaction was warmed slowly to 80° stirring fiveminutes at 80° . The mixture was poured into excess ice/water. Theresulting solid was removed by filtration and washed with water. Theaqueous layer was neutralized with Na₂ CO₃ and then extracted with ethylacetate. The extracts were dried (MgSO₄) and concentrated. The residuewas purified by column chromatography over silica gel using ethylacetate:hexane (1:4) as the eluent. There was obtained 3.4 g of productwhich was combined with the solid which had been removed by filtration.The combined product was recyrstallized from methylene chloride/ethylacetate to afford 61.2 g (84%) of the isatin as an orange solid: m.p.,212°-214°.

d. 7-Bromoisatin oxime

The isatin (61.2 g) described in Example 31c was dissolved in ethanol(550 ml). To this was added hydroxylamine hydrochloridehydroxylaminehydrochloride in 100 ml of water. The mixture was stirredat 80° for 10 minutes, then cooled in an ice-bath. The yellowprecipitate was removed by filtration and dried under high vacuum for 24hours. There was obtained 62.3 g (95%) of the isatin oxime: tlc,Rf=0.20, silica gel, ethyl acetate:hexane (2:3): m.p. greater than 250°.

e. 3-Bromoanthranilonitrile

A suspension of the oxime described in Example 31d in 2.9 liters ofmethylene chloride was treated with 2,6-lutidine (78.1 ml) then cooledto 0° and 112 ml of trifluormethanesulfonic anhydride added. The coolingbath was removed and the mixture heated to vigorous reflux. Afterheating for 3 hours, complete dissolution had occurred and a dark brownsolution remained. The solution was cooled to ambient temperature with awater bath and 174 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) addedslowly. The internal temperature was maintained below 30° during theaddition of the DBU. After stirring for 1 hour at ambient temperature,the mixture was poured slowly with vigorous stirring into excess diluteaqueous sodium bicarbonate. After stirring for several minutes themixture was extracted with methylene chloride. The extracts were dried(MgSO₄) and concentrated. The crude product was purified by columnchromatography over silica gel using methylene chloride as the eluent.The product was triturated with hexane, filtered and dried under vacuumto afford 64.9 g (57%) of the 3-bromoanthranilonitrile: tlc, R_(f)=0.68, silica gel, ethyl acetate:hexane (2:3);

m.p. 119-120° f.2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-bromobenzonitrile (Formula II,A=formula Ia, X=N, n=1

Ra=Br, Rb=propyl)

The procedure described in Example 10f was followed except for thefollowing changes or substitutions: the product from Example 31e (8.91g) was used instead of 2-amino-3-pentylbenzonitrile:3-carboethoxy1-propyl-2,4-dioxopyrrolidine (3.19 g) was used instead ofthe amount indicated in Example 10f; toluene (40 ml instead of 3 ml);acetonitrile (1.5 liters instead of 400 ml); and p-toluenesulfonic acid(0.13 g). After completion of the reaction and isolation of the crudeproduct as described in Example 10f, the product was purified by columnchromatography over silica gel using ethyl acetate:hexane (1:3) as theeluent. There was obtained 2.1 g (29%) of the product as beige crystals.Unreacted 3-bromoanthranilonitrile (Example 31e) was recovered in 81%yield (7.22 g): tlc (product), R_(f) =0.13, silica gel, ethylacetate:hexane (1:1).

9-Amino-2,3-dihydro-5-bromo-2-propylpyrrolo-[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n= 1, Ra=Br, Rb=propyl, Rc=H).

The procedure described in Example 7a was followed except for thefollowing changes or substitutions: the enamine from Example 31f (2.22g) was used instead of the enamine in Example 7a: NaH (0.33 g, 55% inoil instead of 0.17 g), tetrahydrofuran (7 ml instead of 2 ml), cadmiumchloride (1.52 g instead of 0.81 g), dimethylformamide (0.5 ml), andtoluene (7 ml instead of the amount indicated in Example 7a). Aftercompletion of the reaction and isolation of the crude product asdescribed in Example 7a, the product was purified by columnchromatography over silica gel using ethyl acetate:hexane (1:1) as theeluent. Trituration of the product with diethyl ether afforded 1.37 g(62%) of a light brown solid: tlc, R_(f) =0.24, silica gel, ethylacetate:hexane (1:1); m.p. 221°-226° (with decomposition).

Analysis calculated for: C₁₄ H₁₄ N₃ OBr C, 52.21: H, 4.41; N, 13.12,Found: C, 52.46: H, 4.42; N, 13.10.

Examples 32-34

The process described in Example 31a was repeated for the synthesis ofcompounds of formula I where A=formula Ia, Rb=propyl, Rc=H, X=N, n=1,and Ra is selected from 4,4,4-trifluorobutyl (Example 32),4-fluorobenzyl (Example 33), and 3-butenyl (Example 4) by substitutingthe appropriate Grignard reagents for the3-trifluoromethylbutylmagnesium bromide used in Example 31a. The resultsof these Examples are included in Table VI.

                                      TABLE VI                                    __________________________________________________________________________                   Quinoline                                                                          m.p.                                                      Example                                                                            Ra        Yield                                                                              Quinoline                                                                           Elemental Analysis                                  __________________________________________________________________________    32   4,4,4-trifluorobutyl                                                                    34%  134-136°*                                                                    Calculated for C.sub.18 H.sub.20 N.sub.3                                      OF.sub.3                                                                      C, 61.55; H, 5.74; N, 11.96                                                   Found: C, 61.28; H, 5.74; N, 11.81                  33   4-fluorobenzyl                                                                          36%   222-224°**                                                                  Calculated for C.sub.21 H.sub.20 N.sub.3 OF                                   C, 72.19; H, 5.77; N, 12.03                                                   Found: C, 72.19; H, 5.79; N, 12.05                  34   3-butenyl 32%  116-120°*                                                                    Calculated for C.sub.18 H.sub.21 N.sub.3 O                                    C, 73.19; H, 7.17; N, 14.23                                                   Found: C, 72.98; H, 7.14; N, 14.21                  __________________________________________________________________________     *Recrystallized from tertbutylmethyl ether/hexane                             **Recrystallized for ethyl acetate/hexane                                

Example 35 a.9-Amino-2,3-dihydro-5-(3-pentynyl)-2-propylpyrrolo[3,4-b]quinolin-1-one(Formula I,

A=formula Ia, X=N, n=1, Ra=3-pentynyl, Rb=propyl, Rc=H)

To a suspension of magnesium turnings (1.16 g) in tetrahydrofuran (10ml) at 0° was added dropwise 1-bromo-3-pentyne (6.4 g). Following theaddition the mixture was stirred 2 hours at 0° to ensure completeformation of the Grignard reagent. The reagent was transferred viacannula to a solution of zinc bromide (9.68 g) in tetrahydrofuran (10ml) maintained at 0° . The thick, white mixture was warmed to ambienttemperature and stirred for 30 minutes. To this was addeddichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (0.23 g)and the mixture was stirred for 5 minutes. The product described inExample 35d (2.0 g) was added all at once and the mixture warmed to 40°. After 2 hours the mixture was cooled and several milliliters ofsaturated aqueous NH₄ Cl was added slowly. Excess aqueous dsodiumethylenediaminetetraacetic acid was added and the mixture was stirredfor 30 minutes. The reaction was extracted with ethyl acetate and thelayers separated. The ethyl acetate layer was washed with brine, dried(Na₂ SO₄) and concentrated. The crude product was purified by columnchromatography over silica gel followed by recrystallization fromtert-butylmethyl ether/hexane to afford 0.69 g of a crystalline solid(41%); m.p. 147°-149°.

Analysis calculated for: C₁₉ H₂₁ N₃ O: C, 74.24; H, 6.84; N, 13.67;Found: C, 74.09: H, 6.69; N, 13.59.

b. 3-Iodoanthranilonitrile

The processes described in Examples 31b-31e were repeated for thesynthesis of 3-iodoanthranilenitrile by substituting 2-iodoaniline for2-bromoaniline in Example 31b. The remainder of the processes (Examples31b-e) required identical reaction conditions and proportions ofreagents as described in Examples 31b-e. The product was obtained in a27% overall yield: m.p. 122°-124°.

c. 2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-iodobenzonitrile (FormulaII, A=formula Ia, X=N, n=1, Ra=iodo, Rb=propyl)

The procedure described in Example 10f was followed except for thefollowing changes or substitutions: the product from Example 35b (20 g)was used instead of 2-amino-3-pentylbenzonitrile; 3-carboethoxy1-propyl-2,4-dioxopyrrolidine (10 g) was used instead of the amountindicated in Example 10f; toluene (75 ml instead of 3 ml), acetonitrile(2 liters instead of 400 ml) and catalytic p-toluensulfonic acid. Aftercompletion of the reaction and isolation of the crude product asdescribed in Example 10f, the product was purified by trituration withmethylene chloride. There were obtained 5.83 g (34%) of product; tlc,R_(f) =0.16, silica gel, ethyl acetate:hexane (1:1); m.p. 165°-171°.

d. 9-Amino-2,3-dihydro-5-iodo-2-propylpyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=I, Rb=propyl, Rc=H)

The procedure described in Example 7a was followed except for thefollowing changes or substitutions: the enamine from Example 35c (5.75g) was used instead of the enamine in Example 7b; NaH (0.8 g, 55% inoil, instead of 0.17 g), tetrahydrofuran (40 ml instead of 2 ml),cadmium chloride (3.59 g instead of 0.81 g), and toluene (10 ml insteadof the amount indicated in Example 7a). After completion of the reactionand isolation of the crude product as described in Example 7a, theproduct was purified by trituration with methylene chloride. There wasobtained 1.16 g (20%) of a light brown solid; tlc, R_(f) =0.59, silicagel, ethyl acetate:hexane (1:1); m.p.=117°-119°.

EXAMPLE 36 a.9-Amino-2,3-dihydro-5-(2-methylpropyl)-2-(2-propenyl)cyclopenta[b]-quinolin-1-one(Formula I, with A=formula Ia, X=CH, n=1, Ra=2-methylpropyl,Rb=2-propenyl, Rc= H)

To a 0° solution of dry ZnBr₂ (12.5 g) in tetrahydrofuran (25 ml) wasadded dropwise a solution of 2-methylpropylmagnesium chloride (27.7 ml,2.0M in ether). The mixture was warmed to ambient temperature withstirring for 90 minutes. To this was addeddichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (0.20 g)and the reaction was stirred for 5 minutes. The product from Example 36c(1.76 g) was added all at once and the mixture stirred overnight atambient temperature. After cooling to 0°, cold aqueous saturated NH₄ Clwas added slowly followed by disodium ethylenediominetetraacetic acidand ethyl acetate. The ethyl acetate layer was dried (MgSO₄) andconcentrated. The crude product was purified by column chromatographyover silica gel using ethyl acetate:hexane (1:1) as the eluent.Recrystallization from tetrahydrofuran afforded an off-white powder(0.60 g, 37%); tlc, R_(f) =0.49 silica gel, ethyl acetate:hexane (1:3);m.p. 123°-124°.

Analysis calculated for: C₁₉ H₂₂ N₂ O: C, 77.52; H, 7.53: N, 9.52;Found: C, 77.40; H, 7.58; N, 9.40.

b. 2-(1-Oxo-5-(2-propenyl)-2-cyclopenten-3-yl)amino-3-bromobenzonitrile(Formula II, A=formula Ia, X=CH, n=1, Ra=Br, Rb=2-propenyl).

The product described in Example 31e (5.0 g) was refluxed together with4,4-dimethyl-1,3-cyclopentanedione (4.0 g, see U.S. Pat. No. 4,546,104for a description of the synthesis) and p-toluenesulfonic acid (0.15 g)in toluene (25 ml). Evolved water was removed as the azeotrope withtoluene via a Dean-Stark trap. After heating 24 hours, excess toluenewas distilled off and the residue cooled to ambient temperature. Theresidue was partitioned between ethyl acetate and saturated aqueousNaHCO₃. After separation of the layers, the ethyl acetate layer wasdried (Na₂ SO₄) and concentrated. The crude product was purified bycolumn chromatography over silica gel using ethyl acetate:hexane (1:1)to afford the enamine (3.90 g, 48%) as a yellow solid: tlc, R_(f) =0.39,silica gel, ethyl acetate.

c. 9-Amino-5-bromo-2,3-dihydro-2-(2-propenyl)cyclopenta[b]quinolin-1-one(Formula I, A=formula Ia, X=CH, n=1, Ra=bromo, Rb=2-propenyl, Rc=H)

The product prepared in Example 36b (3.90 g) was added as a solution intetrahydrofuran (10 ml) and dimethylformamide (1 ml) to a 0° suspensionof NaH (0.59 g, 55% in oil) in tetrahydrofuran (3 ml). Following theaddition, the mixture was warmed slowly to ambient temperature withstirring for 45 minutes. Cadmium chloride (2.70 g) was added and themixture heated to gentle reflux. Toluene (10 ml) was slowly added andheating continued for 4 hours (bath temperature 110°). After cooling toambient temperature the mixture was partitioned between ethyl acetateand aqueous disodium ethylenediaminetetraacetic acid. The layers wereseparated and the ethyl acetate layer was dried (MgSO₄) andconcentrated. The crude product was purified by column chromatographyover silica gel using ethyl acetate:hexane (1:3) as the eluent. Therewas obtained a yellow solid (3.24 g, 83%); tlc, R_(f) =0.45, silica gel,ethyl acetate:hexane (1:1).

EXAMPLE 379-Amino-2,3-dihydro-5-(2,2-dimethylpropyl)-2-(2-propenyl)cyclopenta[b]quinoline-1-one(Formula I, A=formula Ia, X=CH, n=1, Ra=2,2-dimethylpropyl,Rb=2-propenyl, Rc=H)

The process described in Example 36a was repeated using the followingchanges or substitutions: 2,2-dimethylpropyl magnesium bromide (28.0 ml,2.0M in ether) was used instead of 2-methylpropylmagnesium chloride. Allother amounts of reagents were identical to Example 36a. After workingup and isolating the crude product as described in Example 36a, thematerial was purified by column chromatography over silica gel usingethyl acetate:hexane (1:1) as the eluent. The product was recrystallizedfrom tertbutylmethyl ether/hexane to afford 0.83 g, of a tan solid(49%); tlc, R_(f) =0.47, silica gel, ethyl acetate:hexane (1:1); m.p.137°-138°.

Analysis calculated for: C₂₀ H₂₄ N₂ O: C, 77.89: H, 7.84: N, 9.08;Found: C, 77.70: H, 7.82; N, 8.98.

EXAMPLE 389-Amino-2,3-dihydro-5-phenyl-2-propylpyrrolo[3,4-b]-quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=phenyl, Rb=propyl, Rc=H)

To a slurry of freshly washed NaH (0.22 g, 55% in oil) intetrahydrofuran (15 ml) was added in several portions the bromoquinoline(0.80 g) described in Example 31g. The thick yellow slurry was stirredfor 45 minutes at ambient temperature, followed by the dropwise additionof trifluoroacetic anhydride (0.53 ml). The resulting solution wasstirred for 10 minutes. In a separate reaction flask, phenylmagnesiumbromide (12.5 ml, 2.0M in ether) was added to a solution of ZnBr2 (5-63g) in tetrahydrofuran (10 ml). The mixture was stirred for 1 hour atambient temperature. To the suspension containing the phenylzinc bromidereagent was added dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) (0.09 g) with stirring for 5 minutes. To this mixture was added thesolution containing the N-trifluoroacetyl-substituted-5-bromoquinoline.The resulting mixture was stirred for 4 hours at ambient temperature.Saturated aqueous NH₄ Cl was added slowly followed by ethyl acetate. Theethyl acetate layer was separated, washed with saturated aqueousdisodium ethylenediaminetetraacetic acid and then brine. After drying(MgSO₄), the solution was filtered through a small plug of diatomaceousearth (Celite) surmounted with silica gel to afford, afterconcentrating, a brown solid. This material was taken up in methanol (6ml) followed by the addition of KOH (0.32 g, powdered). The solution waswarmed to 60° and stirred for 7 hours. After cooling to ambienttemperature, the mixture was partitioned between ethylacetate:tetrahydrofuran (1:1) and water. The separated organic phase waswashed with water, then washed with brine. After drying (Na₂ SO₄) andconcentrating, the crude product was purified by column chromatographyover silica gel using ethyl acetate:hexane (1:1) as the eluent. Therewas obtained after recrystallization from ethyl acetate:diethyl ether,0.65 g of a fluffy white solid (82%); tlc, R_(f) =0.39, silica gel,ethyl acetate:hexane (1:1): m.p. 219°-223°.

Analysis calculated for: C₂₀ H₁₉ N₃ O.02 H₂ O: C, 74.84; H, 6.09; N,13.09; Found: C, 75.01; H, 6.10; N, 12.95.

EXAMPLES 39-42

The process described in Example 38 was repeated for the synthesis ofcompounds of formula I where A=formula Ia, Rb=propyl, X=N, Rc=H, n=1,and Ra is selected from 4-fluorophenyl (Example 39), 4-chlorophenyl(Example 40), (1E)-propenyl (Example 41) and 4-methoxyphenyl (Example42) by substituting the appropriate Grignard reagent for thephenylmagnesium bromide used in Example 38. The results of theseExamples are included in the following Table VII.

                                      TABLE VII                                   __________________________________________________________________________    Example                                                                            Ra       Yield                                                                             m.p. Elemental Analysis                                     __________________________________________________________________________    39   4-fluorophenyl                                                                         88% 171-183°.sup.1                                                              Calculated for                                                                C.sub.20 H.sub.18 FN.sub.3 O.H.sub.2 O: C, 68.32;                             H, 5.68; N, 11.95                                                             Found: C, 68.48; H, 5.71; N, 11.62                     40   4-chlorophenyl                                                                         73% 179-183°.sup.2                                                              Calculated for                                                                C.sub.20 H.sub.18 N.sub.3 OCl.0.25H.sub.2 O: C,                               67.41; H, 5.23; N, 11.79                                                      Found: C, 67.77; H, 5.16; N, 11.38                     41   (1E)-propenyl                                                                          32% 199-200°.sup.3                                                              Calculated for                                                                C.sub.17 H.sub.19 N.sub.3 O.0.6H.sub.2 O: C,                                  69.87; H, 6.97; N, 14.38                                                      Found: C, 69.79; H, 6.56; N, 14.10                     42   4-methoxyphenyl                                                                        59% 181-183°.sup.4                                                              Calculated for                                                                C.sub.21 H.sub.21 N.sub.3 O.sub.2.0.7H.sub.2 O: C,                            70.06; H, 6.27; N, 11.67                                                      Found: C, 70.21; H, 6.08; N, 11.70                     __________________________________________________________________________     .sup.1 Recrystallized from methanol/water                                     .sup.2 Recrystallized from ethyl acetate/tertbutyl methyl ether               .sup.3 Recrystallized from ethyl acetate/methylene chloride/hexane            .sup.4 Recrystallized from tertbutyl methyl ether/pentane                

EXAMPLE 43 a.9-Amino-2-cyclopropylmethyl-2,3-dihydro-5-(2-methylpropyl)pyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=2-methylpropyl,Rb=cyclopropylmethyl, Rc=H)

The procedure described in Example 7a was followed except for thefollowing changes or substitutions: the enamine from Example 31d (2.19g) was used instead of the enamine from Example 7a; NaH (0.36 g, 55% inoil instead of 0.17 g), tetrahydrofuran (15 ml instead of 2 ml), cadmiumchloride (1.6 g instead of 0.81 g), and toluene (10 ml instead of theamount indicated in Example 7a). After completion of the reaction andisolation of the crude product as described in Example 7a, the productwas purified by column chromatography over silica gel using ethylacetate:hexane (1:1) as the eluent. Recrystallization from methylenechloride/hexane afforded 1.61 g (77%) of a white solid: m.p. 157°-158°.

Analysis calculated for: C₁₉ H₂₃ N₃ O: C, 73.76; H, 7.49; N, 13.58;Found: C, 73.73: H, 7.54; N, 13.58.

b. 3-(2-Methyl-1-propenyl)-2-aminobenzonitrile

(Formula IV, A=formula Ia, Ra=2-methyl-1-propenyl)

To a warm (about 50°) suspension of magnesium turnings (0.99 g) in 3 mltetrahydrofuran was added dropwise 2-methyl-1-bromopropene (5.54 g). Thereaction became exothermic during the addition. Following addition ofthe bromide, the mixture was heated at 50°-60° for 1 hour. After coolingto about 30°-35°, a solution of ZnBr₂ (9.23 g) in tetrahydro-furan (20ml) was added. The thick white mixture was stirred for 2 hours atambient temperature, thendichloro-[1,1'-bis(diphenylphosphino)]palladium (II) (0.17 g) was added.After 5 minutes at ambient temperature, 3-iodo-2-aminobenzonitrile (theproduct from Example 35b (1 g)) was added in tetrahydrofuran (2 ml). Thereaction mixture was stirred for 30 minutes at ambient temperature, thenquenched by followed by a few milliliters of aqueous disodiumethylenediaminetetraacetic acid. After stirring for 30 minutes, themixture was extracted with methylene chloride. After washing theextracts with brine, they were dried (Na₂ SO₄) and concentrated. Theresidue was chromatographed over silica gel using methylene chloride asthe eluent to leave 0.69 g (98%) of a yellow solid; tlc, R_(f) =0.40,silica gel, CH₂ Cl₂ :hexane (1:1).

c. 3-(2-Methylpropyl)-2-aminobenzonitrile (Formula IV, A=formula Ia,Ra=2-methylpropyl)

The product from Example 43b (9.4 g) was hydrogenated over 10% palladiumon carbon (0.5 g) in ethanol (200 ml) at 3 atmospheres. After about 20hours, the mixture was filtered through diatomaceous earth (Celite) andconcentrated. Purification by column chromatography over silica gelusing methylene chloride as the eluent afforded 7.8 g (78%) of product;tlc, R_(f) =0.46, CH₂ Cl₂ :hexane (1:1).

d.2-(1-Cyclopropylmethyl-2-oxo-3-pyrrolin-4-yl)amino-3-(2-methylpropyl)benzonitrile(Formula II, A=formula Ia, X=N, n=1, Ra=2-methylpropyl,Rb=cyclopropylmethyl)

The procedure described in Example 10f was followed except for thefollowing changes or substitutions: the product from Example 43c (1.6 g)was used instead of 2-amino-3-pentyl-benzonitrile:3-carboethoxy-1-cyclopropyl-2,4-dioxopyrrolidine (1.89 g, preparedaccording to the procedure of Examples 26b-c by substituting ethylN-cyclopropylglycinate for ethyl N-benzylglycinate) was used instead ofthe 3-carboethoxy-1-propyl-2,4- dioxopyrrolidione used in Example 10f;toluene (15 ml instead of 3 ml), acetonitrile (500 ml instead of 400 ml)and catalytic p-toluene-sulfonic acid. After completion of the reactionand isolation of the crude product as described in Example 10f, theproduct was purified by column chromatography over silica gel usingethyl acetate:hexane (1:1) as the eluent. There was obtained 2.19 g(84%) of the product: tlc, R_(f) =0.43, silica gel, ethyl acetate:hexane(1:1).

EXAMPLE 44 a.9-Amino-2,3-dihydro-5-(2-propenyl)-2-propylpyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=2-propenyl, Rb=propyl, Rc=H)

The procedure used in Example 7a was followed except for the followingchanges or substitutions: the enamine from Example 44c (1.72 g) was usedinstead of the enamine in Example 7a; NaH (0.29 g, 55% in oil instead of0.17 g), tetrahydrofuran (6 ml instead of 2 ml), cadmium chloride (1.34g instead of 81 g), dimethylformamide (0.5 ml) and toluene (7 ml insteadof the amount indicated in Example 7a). After completion of the reactionand isolation of the crude product as described in Example 7a, theproduct was purified by column chromatography over silica gel usingethyl acetate:hexane (1:3 to 1:1 gradient) as the eluent. There wasobtained 0.80 g (47%) of the acetate:hexane (1:1); m.p. 152°-152.5°.

Analysis calculated for: C₁₇ H₁₉ N₃ O: C, 72.57; H, 6.81; N, 14.93;Found: C, 72.28; H, 6.79; N, 14.86.

b. 3-(2-Propenyl)-2-aminobenzonitrile (Formula IV, A=formula Ia,Ra=2-propenyl)

The procedure described in Example 43b was followed except for thefollowing changes or substitutions: 2-bromopropene (7.3 ml) was usedinstead of 2-methyl-1-bromopropene: magnesium (2.19 g instead of 0.99g), ZnBr2 (18.5 g instead of 9.23 g) tetrahydrofuran (90 ml totalinstead of the amount used in Example 43b),dichloro-[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (0.60 ginstead of 0.17 g), and 3-iodo-2-aminobenzonitrile (5.0 g instead of theamount used in Example 43b). Following completion of the reaction andisolation of the crude product as described in Example 43b, the productwas purified by column chromatography over silica gel using ethylacetate: hexane (3:20) as the eluent. There was obtained 3.06 g (94%) ofthe product as a light yellow oil; tlc, R_(f) =0.21, silica gel, ethylacetate:hexane (1:1).

c. 2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-(2-propenyl)benzonitrile(Formula II, A=formula Ia, X=N, n=1, Ra=2-propenyl, Rb=propyl)

The procedure described in Example 10f was followed except for thefollowing changes or substitutions: the product from Example 44b (3.0 g)was used instead of the 2-amino-3-pentylbenzonitrile of Example 10f;3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (5.25 g instead of theamount used in Example 10f), acetonitrile (100 ml instead of the amountused in Example 10f), toluene (20 ml instead of the amount used inExample 10f) and catalytic p-toluenesulfonic acid were also used. Aftercompletion of the reaction as described in Example 10f, the crudeproduct was purified by column chromatography over silica gel usingethyl acetate:hexane (1:1) as the eluent. There was obtained 1.72 g(32%) of product: tlc, R_(f) =0.09, silica gel, ethyl acetate:hexane(1:1).

EXAMPLE 459-Amino-2,3-dihydro-2-propyl-5-(2-propyl)pyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=2-propyl, Rb=propyl, Rc=H)

The product from Example 44a (0.74 g) was hydrogenated on a Parr shakerover 5% palladium on carbon (0.10 g) in ethanol (20 ml) at about 3atmospheres of hydrogen. After 1.5 hours the reaction was removed fromthe Parr shaker and filtered. After concentrating, the product waspurified by column chromatography over silica gel using ethylacetate:hexane (1:3) as the eluent. Recrystallization fromtert-butylmethyl ether afforded 0.42 g (57%) of the product as whiteneedles; tlc, R_(f) =0.37, silica gel, ethyl acetate:hexane (1:1); m.p.177°-178°.

Analysis calculated for: C₁₇ H₂₁ N₃ O: C, 72.06; H, 7.47; N, 14.83;Found: C, 71.61; H, 7.42; N, 14.92.

EXAMPLE 46 a.9-Amino-2,3-dihydro-5-(2-methyl-1-propenyl)-2-propylpyrrolo[3,4-b]quinoline-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=2-methyl-1-propenyl, Rb=propyl,Rc=H)

To a suspension of NaH (1.31 g, 55% in oil, washed with tetrahydrofuran)in tetrahydrofuran (30 ml) at 0° was added in several solid portions,the enamine described in Example 46b (8.08 g). Following the additionthe mixture was warmed to ambient temperature and stirred for 30minutes. Dimethylformamide (1 ml) was added followed by cadmium chloride(6.02 g). The mixture was warmed to reflux, then toluene (30 ml) wasadded slowly. The reaction was heated to reflux with stirring for 1hour. After cooling to ambient temperature, saturated aqueous NH₄ Cl wasadded followed by aqueous disodium ethylenediaminetetraacetic acid.Aqueous sodium bicarbonate was added to adjust the pH to 8, then themixture extracted with ethyl acetate/tetrahydrofuran. The layers wereseparated with the organic phase dried (MgSO₄) and concentrated to leavethe crude product. The product was purified by column chromatographyover silica gel using ethyl acetate:methylene chloride (1:3) as theeluent. Recrystallization from ethyl acetate/tertbutylmethyl etherafforded 3.67 g (45%) of the product: tlc, R_(f) =0.29, silica gel,ethyl acetate:hexane (1:1): m.p. 219°-220°.

Analysis calculated for: C₁₈ H₂₁ N₃ O: C, 73.19; H, 7.17; N, 14.23;Found: C, 72.85; H, 7.12; N, 13.57.

b.2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-(2methyl-1-propenyl)benzonitrile(Formula II, A=formula Ia, X=N, n=1, Ra=2-methyl-1-propenyl, Rb=propyl)

Freshly prepared 1-propyl-2,4-dioxopyraolidione (prepared by heating3-carboethoxy-1-propyl-2,4-dioxopyrrolidione (17.43 g) in acetonitrile(3 liters) as described in Example le) was dissolved in toluene (30 ml)and added dropwise over a 1 hour period to a refluxing mixture of theproduct described in Example 43b (6.5 g) and p-toluenesulfonic acid(0.22 g) in toluene (30 ml). The toluene/water azeotrope removed thewater via a Dean-Stark trap. After heating for 4 hours the excesstoluene was distilled off and the reaction mixture cooled to ambienttemperature. The enamine product precipitated out as the reaction cooledand was removed by filtration to afford 6.12 g. The filtrate wasextracted with ethyl acetate which was washed with aqueous saturatedNaHCO₃ and dried (MgSO₄). After filtering and concentrating, the residuewas purified by column chromatography over silica gel using ethylacetate: hexane (1:1) as the eluent. There was obtained an additional1.44 g of product for a combined yield of 68% (7.56 g); tlc, R_(f)=0.11, silica gel, ethyl acetate:hexane (1:1).

EXAMPLES 47-56

The process described in Example 46 was repeated for the synthesis ofcompounds of formula I where A=formula Ia, Ra=2-methyl-1-propyl, Rc=H,X=N, n=1, and Rb=the values listed in Table VIII under the columnheading Rb. The required 3-carboethoxy-1-substituted-2,4-pyrrolidioneswere obtained by the process described in Examples 26b-c by substitutingthe appropriate ethyl N-substituted glycinate for ethylN-benzyleglycinate used in Examples 26b-c. The results of these Examplesare included in Table VIII.

                                      TABLE VIII                                  __________________________________________________________________________                         Enamine                                                                            Quinoline                                                                          m.p.                                           Example                                                                            Ra        Rb    Yield                                                                              Yield                                                                              Quinoline                                                                            Elemental Analysis for                  __________________________________________________________________________                                          Quinoline                               46   2-methyl-1-propenyl                                                                     propyl                                                                              27   45   219-220°*dec                                                                  Calculated for C.sub.18 H.sub.21                                              N.sub.3 O                                                                     C, 73.19; H, 7.17, N, 14.23                                                   Found: C, 72.85; H, 7.12; N, 13.57      47   2-methyl-1-propyl                                                                       butyl 71   61.5 151-152°**                                                                    Calculated for C.sub.19 H.sub.25                                              N.sub.3 O                                                                     C, 73.28; H, 8.09; N, 13.49                                                   Found: C, 72.98, H, 8.05; N, 13.26      48   2-methyl-1-propyl                                                                       3-chloro-                                                                           >99  82.9 168-170°**                                                                    Calculated for C.sub.22 H.sub.22                                              N.sub.3 OCl                                            benzyl                 C, 69.56 H, 5.84; N, 11.06                                                    Found: C, 69.22, H, 5.95; N, 10.90      49   2-methyl-1-propyl                                                                       2-methoxy                                                                           63.8 68   139-142°**                                                                    Calculated for C.sub.18 H.sub.23                                              N.sub.3 O.sub.2.0.1H.sub.2 O                           ethyl                  C, 68.59; H, 7.42; N, 13.33                                                   Found: C, 68.39; H, 7.38; N, 13.39      50   2-methyl-1-propyl                                                                       4-fluoro-                                                                           74   97   170-172.5***                                                                         Calculated for C.sub.22 H.sub.22                                              N.sub.3 OF                                             benzyl                 C, 72.71; H, 6.10; N, 11.56                                                   Found: C, 72.38; H, 6.16; N, 11.36      51   2-methyl-1-propyl                                                                       4-methoxy-                                                                          89   63.2 170-173°**                                                                    Calculated for C.sub.23 H.sub.25                                              N.sub.3 O.sub.2                                        benzyl                 C, 73.58; H, 6.71; N, 11.19                                                   Found: C, 73.33; H, 6.68; N, 11.09      52   2-methyl-1-propyl                                                                       4-chloro-                                                                           87.4 70.2 188-190°**                                                                    Calculated for C.sub.22 H.sub.22                                              N.sub.3 OCl                                            benzyl                 C, 69.56; H, 5.84; N, 11.06                                                   Found: C, 69.48; H, 5.93; N, 10.98      53   2-methyl-1-propyl                                                                       3-methoxy-                                                                          86   74.4 149-150°**                                                                    Calculated for C.sub.23 H.sub.25                                              N.sub.3 O.sub.2                                        benzyl                 C, 73.58; H, 6.71; N, 11.19                                                   Found: C, 73.17; H, 6.72; N, 11.59      54   2-methyl-1-propyl                                                                       2-flouro-                                                                           82.5 59   168-171°**                                                                    Calculated for C.sub.22 H.sub.22                                              N.sub.3 OF                                             benzyl                 C, 72.71; H, 6.10, N, 11.56                                                   Found: C, 72.60; H, 6.29; N, 11.55      55   2-methyl-1-propyl                                                                       3-methoxy-                                                                          74   90.7 123-124°**                                                                    Calculated for C.sub.19 H.sub.25                                              N.sub.3 O.sub.2                                        propyl                 C, 69.70; H, 7.70; N, 12.83                                                   Found: C, 69.59; H, 7.90; N, 12.75      56   2-methyl-1-propyl                                                                       2-furyl-                                                                            98.4 64   165-167°**                                                                    Calculated for C.sub.20 H.sub.21                                              N.sub.3 O.sub.2                                        methyl                 C, 71.62; H, 6.31; N, 12.53                                                   Found: C, 71.43; H, 6.27; N,            __________________________________________________________________________                                          12.51                                    *Recrystallized from ethyl acetate/tertbutylmethyl ether                      **Recrystallized from methylene chloride/hexane                               ***Recrystallized from tertbutylmethylether/hexane                       

EXAMPLE 57 a.9-Amino-2,3-dihydro-2-(2-propynyl)-5-(2-methylpropyl)pyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=2-methylpropyl, Rb=2-propynyl,Rc=H)

To a suspension of NaH (0.395 g, 55% in oil, prewashed with hexane) indimethylsulfoxide (5 ml) was added slowly the product described inExample 57b (2.0 g) dissolved in warm (35°) dimethylsulfoxide (20 ml).The mixture was stirred for 1 hour at 35° then added to a second flaskcontaining 2-propynyl bromide (1.04 ml of an 80% solution in toluene) indimethylsulfoxide (5 ml). The reaction mixture was heated at 35° for 2hours then cooled to ambient temperature and quenched by pouring intodilute aqueous NH₄ Cl. The mixture was extracted with ethyl acetate withthe organic phase washed once with water, then brine. After drying(MgSO₄) and concentrating, the crude product was chromatographed oversilica gel using ethyl acetate:hexane (1:1) as the eluent.Recrystallization from ethyl acetate/hexane afforded 0.55 g (24%) of awhite solid; tlc, R_(f) =0.62, silica gel, ethyl acetate:hexane (1:1):m.p. 198°-199°.

Analysis calculated for: C₁₈ H₁₉ N₃ O: C, 73.69; H, 6.53; N, 14.32;Found: C, 73.45; H, 6.50; N, 13.99.

b. 9-Amino-5-(2-methylpropyl)-2,3-dihydropyrrolo-[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=2-methylpropyl, Rc=H, Rb=H)

The product from Example 28a (1.0 g) was dissolved in trifluoroaceticacid (40 ml) followed by warming to 40°. After stirring at 40° for 1.5hours, the volatiles were removed and the residue partitioned betweenethyl acetate/methanol and aqueous NaHCO₃. The organic layer wasseparated, concentrated and dried under high vacuum overnight to afford0.35 g (44%) of product.

EXAMPLE 58 a.9-Amino-2-cyclopropylmethyl-2,3-dihydro-5-propylpyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=propyl, Rb=cyclopropylmethyl,Rc=H)

The procedure described in Example 7a was followed except for thefollowing changes or substitutions: the enamine from Example 58d (1.3 g)was used instead of the enamine from Example 7a; NaH (0.22g, 55% in oilinstead of 0.17 g), tetrahydrofuran (7.5 ml instead of the amountindicated in Example 7a), cadmium chloride (1.01 g instead of 0.81 g)and toluene (5 ml instead of the amount indicated in Example 7a). Aftercompletion of the reaction and isolation of the crude product asdescribed in Example 7a, the product was purified by columnchromatography over silica gel using ethyl acetate:hexane (2:3) as theeluent. Recrystallization from tert-butylmethyl ether afforded 1.02 g(79%) of product; tlc, R_(f) =0.48, silica gel, ethyl acetate:hexane(1:1); m.p. 128°-130°.

Analysis calculated for: C₁₈ H₂₁ N₃ O: C, 72.75: H, 7.19: N, 14.14;Found: C, 72.70: H, 7.10; N, 14.16.

b. 3-(1-Propenyl)-2-aminobenzonitrile (Formula IV, A=formula Ia,Ra=1-propenyl)

The procedure described in Example 43b was followed with the followingchanges or substitutions: 1-bromopropene (6.14 ml of an E,Z-mixtureinstead of the 2-methyl-1-bromopropene used in Example 43b), magnesium(1.92 g instead of 0.99 g), ZnBr₂ (16.15 g instead of 9.23 g),dichloro-[1,1-bis(diphenylphosphino)ferrocene]palladium (II) (0.42 ginstead of 0.17 g), tetrahydrofuran (47 ml instead of the amount used inExample 43b) and 3-iodo-2-aminobenzonitrile (3.5g, described in Example35b) were used. After completion of the reaction and isolation of thecrude product as described in Example 43b, the product was purified bycolumn chromatography over silica gel using ethyl acetate:hexane (3:17)to afford 2.20 g (97%) of a light yellow oil: tlc, R_(f) =0.32, silicagel, ethyl acetate:hexane (3:17).

c. 3-Propyl-2-aminobenzonitrile (Formula IV, A=formula Ia, Ra=propyl)

The product from Example 58b (2.20 g) was hydrogenated over 10%palladium on carbon (0.176 g) in ethanol (25 ml) at about 3 atmospheres.After 1 hour at ambient temperature the mixture was filtered andconcentrated to leave an oil. Purification by column chromatography oversilica gel afforded 2.20 g (98%) of a low melting solid; tlc, R_(f)=0.38, silica gel, ethyl acetate:hexane (3:17); m.p. about 33°.

d.2-(1-Cyclopropylmethyl-2-oxo-3-pyrrolin-4-yl)amino-3-propyl-benzonitrile(Formula II, A=formula Ia, X=N, n=1, Ra=propyl, Rb=cyclopropylmethyl)

The procedure described in Example 10f was followed except for thefollowing changes or substitutions: the product from Example 58c (0.85g) was used instead of 2-amino-3-pentyl-benzonitrile used in Example10f; 3-carboethoxy-1-cyclopropyl-Z,4-dioxopyrrolidione (1.8 g, preparedaccording to the procedure of Examples 26b-c by substituting ethylN-cyclopropylmethylglycinate for ethyl N-benzylglycinate) was usedinstead of 3-carboethoxy-1-propyl-2,4-dioxopyrrolidione used in Example10f; toluene (15 ml instead of the amount used in Example 10f) andcatalytic p-toluenesulfonic acid. After completion of the reaction andisolation of the crude product as described in Example 10f, the productwas purified by column chromatography over silica gel using ethylacetate:hexane (1:1) as the eluent. There was obtained 1.31 g (84%) ofthe product; tlc, R_(f) =0.1, silica gel, ethyl acetate:hexane (1:1).

EXAMPLES 59-61

The processes described in Examples 58a through 58d were repeated forthe synthesis of compounds of formula I where A=formula Ia, Ra=propyl,Rc=H, X=N, n=1, and Rb is selected from 2-propenyl (Example 59),4-methoxybenzyl (Example 60), and 2-furylmethyl (Example 61) bysubstituting the appropriate ethyl N-substituted glycinates for ethylN-benzylglycinate in Examples 26b-c for the synthesis of3-carboethoxy-1-substituted-2,4-dioxopyrrolidiones. Substitution ofthese 3-carboethoxy-1-substituted-2,4-dioxopyrrolidiones in Example 58dfor 3-carboethoxy-1-cyclopropylmethyl-2,3-dioxopyrrolidione givesintermediates of the formula II where A=formula Ia, Ra=propyl, X=N, n=1,and Rb=the values stated above for Examples 59-61. The results of theseExamples are included as shown in in Table IX.

                                      TABLE IX                                    __________________________________________________________________________                   Enamine                                                                            Quinoline                                                                          m.p.                                                 Example                                                                            Ra  Rb    Yield                                                                              Yield                                                                              Quinoline                                                                          Elemental Analysis for Quinoline                __________________________________________________________________________    59   propyl                                                                            2-propenyl                                                                          89   95*  144-145°                                                                    Calculated for C.sub.17 H.sub.19 N.sub.3 O                                    C, 72.57; H, 6.81; N, 14.93                                                   Found: C, 71.78; H, 6.74; N, 14.76              60   propyl                                                                            4-methoxy-                                                                          81    70**                                                                              166-167°                                                                    Calculated for C.sub.22 H.sub.23 N.sub.3                                      O.sub.2                                                  benzyl               C, 73.11; H, 6.41; N, 11.63                                                   Found: C, 72.57; H, 6.45; N, 11.90              61   propyl                                                                            2-furyl-                                                                            84   70*  144-149°                                                                    Calculated for C.sub.19 H.sub.19 N.sub.3                                      O.sub.2                                                  methyl               C, 71.01; H, 5.96; N, 13.07                                                   Found: C, 70.95; H, 6.08; N,                    __________________________________________________________________________                                  13.10                                            *Recrystallized from methylene chloride/hexane                                **Recrystallized from ethyl acetate                                      

EXAMPLE 62 a.9-Amino-5-butyl-2,3-dihydro-2-(2-propenyl)pyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=butyl, Rb=2-propenyl, Rc=H)

The procedure described in Example 7a was followed except for thefollowing changes or substitutions: the enamine from Example 62d (1.0 g)was used instead of the enamine from Example 7a; NaH (0.17 g, 55% inoil), tetrahydrofuran (8.0 ml instead of the amount indicated in Example7a), cadmium chloride (0.78 g instead of 0.81 g); dimethylformamide (2ml) and toluene (5 ml instead of the amount indicated in Example 7a)were also used. After completion of the reaction and isolation of thecrude product as described in Example 7a, the product was purified bycolumn chromatography over silica gel using ethyl acetate:hexane (2:3)as the eluent. Recrystallization from methylene chloride/hexane afforded0.91 g (84%) of the product; tlc, R_(f) =0.51, silica gel, ethylacetate:hexane (1:1); m.p. 152°-153°.

Analysis calculated for: C₁₈ H₂₁ N₃ O: C, 73.19: H, 7.17; N, 14.23;Found: C, 73.30; H, 7.11; N, 14.2.

b. 3-(1-Butenyl)-2-aminobenzonitrile (Formula IV, A=formula Ia,Ra=1-butenyl)

The procedure described in Example 43b was followed with the followingchanges or substitutions: 1-bromobutene (9.9 g of an E,Z mixture)instead of 2-methyl-1-bromopropene, magnesium (1.9 g instead of 0.99 g),ZnBr₂ (16.6 g instead of 9.23 g),dichloro-[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (0.47 ginstead of 0.17 g), tetrahydrofuran (115 ml instead of the amount usedin Example 43b) and 3-iodo-2-aminobenzonitrile (4.5 g, prepared asdescribed Example 35b). After completion of the reaction and isolationof the crude product as described in Example 43b, the product waspurified by column chromatography over silica gel using methylenechloride:hexane (1:1) as the eluent. There was obtained 3.0 g(quantitative); tlc, R_(f) =0.38, silica gel, methylene chloride: hexane(1:1).

c. 3-Butyl-2-aminobenzonitrile (Formula IV, A=formula Ia, Ra=butyl)

The product from Example 62b (3.0 g) was hydrogenated over 10% palladiumon carbon (0.16 g) in ethanol (60 ml) at about 3 atmospheres. After 1hour at ambient temperature, the mixture was filtered and concentratedto leave an oil. Purification by column chromatography over silica gelafforded 2.95 g (96%) of an oil; tlc, R_(f) =0.38, silica gel, ethylacetate:hexane (3:17).

d. 2-(1-2-Propenyl)-2-oxo-3-pyrrolin-4-yl)amino-3-butylbenzonitrile(Formula II, A=formula Ia, X=N n=1, Ra=butyl, Rb=2-propenyl)

The procedure described in Example 10f was followed except for thefollowing changes or substitutions: the product from Example 62c (0.75g) was used instead of 2-amino-3-pentylbenzonitrile;3-carboethoxy-1-(2-propenyl)-2,4-dioxopyrrolidione (1.36 g preparedaccording to the procedure of Examples 26b-c by substituting ethylN-(2-propenyl)glycinate for ethyl N-benzylglycinate, was used instead of3-carboethoxy-1-propyl-2,4-dioxopyrrolidione), toluene (15 ml instead ofthe amount used in Example 10f) and catalytic p-toluenesulfonic acid.After completion of the reaction and isolation of the crude product asdescribed in Example 10f, the product was purified by columnchromatography over silica gel using ethyl acetate:hexane (2:1) as theeluent. There was obtained 0.75 g (59%) of the product; tlc, R_(f)=0.20, silica gel, ethyl acetate:hexane (1:1).

EXAMPLES 63-64

The processes described in Examples 62a and 62d were repeated for thesynthesis of compounds of formula I where A=formula Ia, Ra=butyl, Rc=H,X=N, n=1, and Rb is selected from cyclopropylmethyl (Example 63) and2-furylmethyl (Example 64) by substituting the appropriate ethylN-substituted glycinates for ethyl N-benzylglycinate as described inExamples 26b-c for the synthesis of3-carboethoxy-1-substituted-2,4-dioxopyrrolidiones. Substitution ofthese 3-carboethoxy-l-(2-propenyl)-2,4-dioxopyrrolidione affordsintermediates of formula II where A=formula Ia, Ra=butyl, X=N, n=1 andRb=the values stated above for Examples 63-64. The results of theseExamples are included in Table X.

                                      TABLE X                                     __________________________________________________________________________                 Enamine                                                                            Quinoline                                                                          m.p.                                                   Example                                                                            Ra Rb   Yield                                                                              Yield                                                                              Quinoline                                                                          Elemental Analysis for Quinoline                  __________________________________________________________________________    63   butyl                                                                            cyclo-                                                                             86   78   143-144°*                                                                   Calculated for C.sub.19 H.sub.23 N.sub.3 O:               propyl-             C, 73.76; H, 7.49; N, 13.58                               methyl-             Found: C, 73.67; H, 7.46; N, 13.54                64   butyl                                                                            2-furyl-                                                                           83.7 69   152-143°*                                                                   Calculated for C.sub.20 H.sub.21 N.sub.3                                      O.sub.2 :                                                 methyl              C, 71.62; H, 6.31; N, 12.53                                                   Found: C, 71.48; H, 6.38; N,                      __________________________________________________________________________                                12.51                                              *Recrystallized from methyl chloride/hexane                              

EXAMPLE 65 a. 9-Amino-2,3-dihydro-5-(4-methylphenyl)-2-propylpyrrolo[34-b]quinolin-1-one (Formula I, A=formula Ia, X=N, n=1,Ra=4-methylphenyl, Rb=propyl, Rc=H)

The procedure used in Example 7a was followed except for the followingchanges or substitutions: the enamine from Example 65c (0.82 g) was usedinstead of the enamine in Example 7a; NaH (0.12 g, 55% in oil instead of0.17 g), tetrahydrofuran (10 ml instead of 2 ml), cadmium chloride 0.054g instead of 0.81 g), dimethylformamide (2 ml) and toluene (8 ml insteadof the amount indicated in Example 7a). After completion of the reactionand isolation of the crude product as described in Example 7a, theproduct was purified by column chromatography over silica gel usingethyl acetate:hexane (1:1) as the eluent. Recrystallization from ethylacetate/tert-butylmethyl 20 ether/hexane afforded 0.65 g (79%) of afluffy white solid: tlc, R_(f) =0.18, silica gel, ethyl acetate:hexane(1:1); m.p. 215°-217°.

Analysis calculated for: C₂₁ H₂₁ N₃ O: C, 76.11; H, 6.39; N, 12.68 ;Found: C, 75.92; H, 6.53: N, 12.60.

b. 3-(4-Methylphenyl)-2-aminobenzonitrile (Formula IV, A=formula Ia,Ra=4-methylphenyl)

To a -78° solution of 4-bromotoluene (1.97 ml) in tetrahydrofuran (20ml) was added dropwise n-butyllithium (8.9 ml, 1.87M in hexane). Afterstirring for 30 minutes at -78° a solution of ZnBr₂ (3.96 g) intetrahydrofuran (20 ml) was added quickly. The solution was warmed toambient temperature then stirred for 1 hour.Dichloro-1,1'-bis[(diphenylphosphino)ferrocene]palladium (II) (0.16 g)was added and the mixture was stirred for 5 minutes. To this was added3-iodo-2-aminobenzonitrile (1.3 g, described in Example 35b as asolution in tetrahydrofuran (3 ml). After stirring for 15 minutes atambient temperature, aqueous NH₄ Cl was added followed by aqueousdisodium ethylenediaminetetraacetic acid, ethyl acetate and enoughaqueous NaHCO₃ to adjust the pH to 8. The layers were separated. Theorganic phase was washed with saturated aqueous disodiumethylenediaminetetraacetic acid then dried over MgSO₄. After filteringand concentrating, the product was purified by column chromatographyover silica gel using ethyl acetate:hexane (1:9) and the eluent. Therewas obtained 0.80 g (72%) of a crystalline solid: tlc, R_(f) =0.61,silica gel, ethyl acetate:hexane (3:17).

c.2-(1-Propyl-2-oxo-3-pyrrolin-4-yl)amino-3-(4-methylphenyl)benzonitrile(Formula II, A=formula Ia, X=N, n=1, Ra=4-methylphenyl, Rb=propyl)

The procedure described in Example 10f was followed except for thefollowing changes or substitutions: the product from Example 65b (0.70g) was used instead of the 2-amino-3-pentyl-benzonitrile used in Example10f; 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (1.07 g instead of theamount used in Example 10f): acetonitrile (250 ml instead of the amountindicated in Example 10f); toluene (5 ml instead of the amount used inExample 10f) and catalytic p-toluenesulfonic acid. After completion ofthe reaction as described in Example 10f, the crude product was purifiedby column chromatography over silica gel using ethyl acetate:hexane(1:1) as the eluent. There was obtained 0.82 g (74%) of an offwhitesolid tlc, R_(f) =0.09, silica gel, ethyl acetate:hexane (1:1).

EXAMPLE 66-68

The process described in Example 65 was repeated for the synthesis ofcompounds of formula I where A=formula Ia, Rb=propyl, Rc=H, X=N, n=1,and Ra is selected from 3-methoxyphenyl (Example 66), 2-methoxyphenyl(Example 67), and 4-N,N-dimethylaminophenyl (Example 68) by substitutingthe aryl bromides 3-bromoanisole (Example 66), 2-bromoanisole (Example67) and 4-bromo-N,N-dimethylaniline (Example 68), respectively, for4-bromotoluene used in Example 65. The results of these Examples areshown in Table XI.

                                      TABLE XI                                    __________________________________________________________________________         Yield    Enamine                                                                            Quinoline                                                                          Quinoline                                             Example                                                                            Anthranilonitrile                                                                      Yield                                                                              Yield                                                                              m.p.  Elemental Analysis of Quinoline                 __________________________________________________________________________    66   94%      50%  76%  189-190°*                                                                    Calculated for C.sub.21 H.sub.21 N.sub.3                                      O.sub.2 :                                                                     C, 72.60; H, 6.09; N, 12.10                                                   Found: C, 72.75; H, 6.30; N, 12.13              67   62%      85%  56%  187-187.5°*                                                                  Calculated for C.sub.21 H.sub.21 N.sub.3                                      O.sub.2.0.3H.sub.2 O:                                                         C, 71.32; H, 6.31; N, 11.24                                                   Found: C, 71.21; H, 6.38; N; 11.18              68   >99%     78%  50%  217-221°*                                                                    Calculated for C.sub.22 H.sub.24 N.sub.4                                      O:                                                                            C, 73.31; H, 6.71; N, 15.54                                                   Found: C, 72.66; H, 6.82; N,                    __________________________________________________________________________                                  15.90                                            *Recrystallized from tertbutylmethyl ether/hexane                        

EXAMPLE 69 a.9-Amino-2,3-dihydro-5-(1-hydroxy-3-methylbutyl)-2-propylpyrrolo[3,4-b]quinolin-1-one(Formula I, A=formula Ia, X=N, n=1, Ra=1-hydroxy-3-methylbutyl,Rb=propyl, Rc=H)

To a -45° suspension of the product described in Example 69b (0.96 g)was added dropwise 2-methylpropylmagnesium chloride (3.56 ml, 2Msolution in ether). Following the addition the mixture was warmed to 0°and stirred for 1 hour. The reaction was poured slowly with stirringinto excess saturated NH₄ Cl then extracted with ethyl acetate. Theextracts were dried (MgSO₄) and concentrated. The crude product waspurified by column chromatography over silica gel using ethylacetate:hexane (1:1) as the eluent. Recrystallization fromtert-butylmethyl ether afforded 0.54 g (46%) of a yellow solid; tlc,R_(f) =0.22, silica gel, ethyl acetate:hexane (1:1); m.p. 135°-148°.

Analysis calculated for C₁₉ H₂₅ N₃ O₂ : C, 69.70; H, 7.70; N, 12.83;Found C, 69.71; H, 7.80; N, 12.38.

b.9-Amino-2,3-dihydro-2-propylpyrrolo[3,4-b]quinolin-1-one-5-carboxaldehyde(FormulaI, A=formula Ia, X=N, n=1, Rb=propyl, Ra=CHO, Rc=H)

The product described in Example 41 (1.0 g) was ozonized at -78° in amixture of methanol (7.5 ml) and methylene chloride (3 ml). Followingcompletion of the ozonolysis) the cooling bath was removed and aqueoussodium sulfite (0.11 g in 3 ml of water) was added all at once. Themixture was warmed to ambient temperature and stirred for 1 hour. Themixture was extracted with methylene chloride. The extracts were dried(MgSO₄) and filtered through a short silica gel plug. Afterconcentrating, there was obtained 0.90 g (quantitative) of the aldehyde;tlc, R_(f) =0.15, silica gel, ethyl acetate:hexane (1:1).

EXAMPLE 70-72

The process described in Example 69 was repeated for the synthesis ofcompounds of formula I where A=formula Ia, Rb=propyl, Rc=H, X=N, n=1,and Ra is selected from 1-hydroxyphenylmethyl (Example 70),1-hydroxy-2-methylpropyl (Example 71), and 1-hydroxypropyl (Example 72)by substituting the Grignard reagents phenylmagnesium bromide (Example70), 2-propylmagnesium chloride (Example 71) and ethylmagnesium bromide(Example 72), respectively, for the 2-methylpropylmagnesium chlorideused in Example 69a. The results of these Examples are shown in TableXII.

                  TABLE XII                                                       ______________________________________                                        Example                                                                              Yield   m.p.      Elemental Analysis                                   ______________________________________                                        70     56%     225-232°*                                                                        Calculated for C.sub.21 H.sub.21 N.sub.3 O.sub.2                              :                                                                             C, 72.60; H, 6.09; N, 12.09                                                   Found: C, 71.78; H, 6.07; N, 12.03                   71     23%     156-157°**                                                                       Calculated for C.sub.18 H.sub.23 N.sub.3 O.sub.2                              :                                                                             C, 68.98; H, 7.48; N, 13.41                                                   Found: C, 68.32; H, 7.30; N, 13.77                   72     43%     176-177°***                                                                      Calculated for C.sub.17 H.sub.21 N.sub.3 O.sub.2                              :                                                                             C, 68.21; H, 7.07; N, 14.04                                                   Found: C, 68.11; H, 7.06; N, 14.05                   ______________________________________                                         *Recrystallized from tertbutylmethyl ether                                    **Recrystallized from ethyl acetate/tertbutylmethyl ether                     ***Recrystallized from tertbutylmethyl ether                             

EXAMPLE 73

The following illustrates representative pharmaceutical dosage formswhich may be used for the therapeutic or prophylactic administration ofa compound of formula I or of a pharmaceutically acceptable salt thereof(hereinafter referred to as `Compound A`):

    ______________________________________                                        a. Tablet 1       mg/tablet                                                   ______________________________________                                        `Compound A`      5                                                           Lactose           88                                                          Magnesium stearate                                                                              1                                                           Polyvinylpyrrolidone                                                                            2                                                           Sodium starch glycollate                                                                        4                                                           ______________________________________                                    

The lactose, sodium starch glycollate and polyvinylpyrrolidone are mixedin a planetary mixer and water added until a suitable mass forgranulation is obtained. The mass obtained is granulated through asuitable size mesh and dried to obtain the optimum moisture content. Themagnesium stearate is then added and the dry granulate is then passedthrough a further screen before final blending and compression to yieldtablets each weighing 100 mg.

    ______________________________________                                        b. Tablet 2       mg/tablet                                                   ______________________________________                                        `Compound A`      250                                                         Lactose           122                                                         Magnesium stearate                                                                               4                                                          Polyvinylpyrrolidone                                                                             8                                                          Sodium starch glycollate                                                                         16                                                         ______________________________________                                    

The tablets are formulated as described in part a. to yield tablets eachweighing 400 mg.

    ______________________________________                                        c. Tablet 3       mg/tablet                                                   ______________________________________                                        `Compound A`      100                                                         Lactose           86                                                          Magnesium stearate                                                                              2                                                           Polyvinylpyrrolidone                                                                            4                                                           Sodium starch glycollate                                                                        8                                                           ______________________________________                                    

The tablets are formulated as described in part a. to yield tablets eachweighing 200 mg. ##STR1##

What is claimed is:
 1. A compound of the following formulawherein: n=1;X=N; Ra is selected from a group consisting of (1-10C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (4-10C)cycloalkylalkyl,(2-10C)hydroxyalkyl, (1-10C)haloalkyl having at least one halo groupwherein the halo group(s) is independently selected from a groupconsisting of fluoro and chloro, (6-10C)aryl, (7-12C)arylalkyl (whereinsaid aryl portion of the aryl or arylalkyl may, optionally, besubstituted by a member selected from a group consisting of (1-4C)alkyl,(1-4C)alkoxy, halogeno and amino optionally substituted independently byone or two of (1-4C)alkyl and wherein the alkyl portion of the arylalkylmay optionally be substitute hydroxy, and furylmethyl or thienylmethylwherein the heteroaryl may optionally be substituted by (1-3C)alkyl; Rbis selected from a group consisting of (1-10C)alkyl (optionallysubstituted by (1-3C)alkoxy), (4-10C)cycloalkyl alkyl, (3-8C)alkenyl,(3-8C)alkynyl, (2-8C)haloalkyl having 1-3 halo group(s) independentlyselected from fluoro and chloro, (2-8C)hydroxy-alkyl, phenyl,phenyl(1-3C)alkyl, (wherein the phenyl portion of phenyl or phenylalkylis optionally substituted by a member selected from a group consistingof halogeno, (1-3C)alkyl and (1-3C)alkoxy), a heteroary(1-3C)alkyl,wherein the heteroaryl portion is furyl or thienyl and may optionally besubstituted by (1-3C)alkyl; and Rc is selected from a group consistingof hydrogen, (1-10C)alkyl and (2-10C)alkanoyl; or a pharmaceuticallyacceptable acid addition salt thereof.
 2. A compound as claimed in claim1 wherein:Ra is selected from a group consisting of (1-6C)alkyl,(4-8C)cycloalkylalkyl, (3-6C)alkenyl, (3-6C)alkynyl, (6-10C)aryl,(7-12C)ary aryl portion of the aryl or arylalkyl may optionally besubstituted by (1-3C)-alkyl, (1-3C)alkoxy, halogeno, or amino optionallysubstituted independently by 1 or 2 of (1-3C)alkyl, and wherein thealkyl portion of the arylalkyl may optionally be substituted byhydroxy); (1-6C)haloalkyl having at least one of fluoro or chloro,(3-6C)hydroxyalkyl, (4-8C)hydroxycycloalkylalkyl, and furylmethyl orthienylmethyl optionally substituted by (1-3C)alkyl; Rb is selected froma group consisting of (2-5C)alkyl optionally substituted by(1-3C)alkoxy, (3-5C)alkenyl, (3-5C)alkynyl, (4-6C)cycloalkyl,(3-5C)haloalkenyl having 1-3 halo group(s), phenyl, phenyl(1-3C)alkyl,(wherein the phenyl poriton of phenyl or phenylalkyl is optionallysubstituted by a member selected from a group consisting of halogeno,(1-3C)alkyl and (1-3C)alkoxy), heteroaryl(1-3C)alkyl wherein theheteroaryl portion is furyl or thienyl and may optionally be substitutedby (1-3C)alkyl; and Rc is selected from a group consisting of hydrogen,(1-6C)alkyl and (2-6C)alkanoyl.
 3. A compound as claimed in claim 2wherein:Ra is selected from a group consisting of (1-6)alkyl,(4-8C)cycloalkyl, (3-6C)alkenyl, (3-6C)alkynyl, phenyl,phenyl(1-2C)alkyl (wherein the phenyl or the phenyl portion of thephenylalkyl may optionally be substituted by a member selected from agroup consisting of fluorine, chloro bromine, methyl, ethyl, propyl,methoxy, ethoxy, propoxy, and amino optionally substituted independentlyby 1 or 2 of (1-3C)alkyl, and wherein the alkyl portion of thephenylalkyl may optionally be substituted by hydroxy), heteroaryalkylselected from a group consisting of 2-thienylmethyl, 3-thienylmethyl; Rbis selected from a group consisting of (2-5C)alkyl optionallysubstituted by (1-3C)alkoxy, (3-5C)alkenyl, (3-5C)alkynyl,(4-6C)cycloalkyl benzyl optionally substituted on the phenyl by a memberselected from a group consisting of fluorine, chlorine, bromine,(1-3C)alkyl and (1-3C)alkoxy, and 2-furylmethyl; and Rc is selected froma group consisting hydrogen, propyl, butyl, acetyl, butyryl and valeryl.4. A compound as claimed in claim 1 wherein:Ra is selected from a groupconsisting of methyl, ethyl, n-propyl, n-butyl, 3-methylbutyl, n-pentyl,2-methylbutyl, 2,2-dimethylpropyl, 2-methylpropyl,3-trifluoromethylbutyl, 4,4,4-trifluorobutyl, 1-hydroxy-3-methylbutyl,1-hydroxpropyl, 3-butenyl, 1-propanyl, 2-propenyl, 2-methyl-1-propenyl,3-pentynyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-thienylmethyl, 3-thienylmethyl, benzyl, phenethyl, 4-fluorobenzyl,1-hydroxy-1-phenylmethyl, phenyl, 4-chlorophenyl, 4-fluorophenyl,4-methoxyphenyl, 4-methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, and4-dimethylaminophenyl; Rb is selected from a group consisting of ethyl,n-propyl, n-butyl, 2-methoxyethyl, 3-methoxypropyl, 2-propenyl,2-propynyl, 2-butynyl, cyclopropylmethyl, benzyl, 2,4-dimethoxybenzyl,3-chlorobenzyl, 4-fluorobenzyl, 4-methoxybenzyl, 4-chlorobenzyl,3-methoxybenzyl, 2-florobenzyl and 2-furylmethyl; and Rc is hydrogen. 5.A compound as claimed in claim 1, 2, 3 or 4 wherein Rb is propyl, butylor 2-propenyl.
 6. A compound as claimed in claim 1 selected from a groupconsisting of:(a) a compound wherein Ra=3-methylbutyl, Rb=propyl andRc=hydrogen; (b) a compound wherein Ra=2-methylpropyl, Rb=propyl andRc=hydrogen; (c) a compound wherein Ra=cyclopropylmethyl, Rb=propyl andRc=hydrogen; and (d) a compound wherein Ra=propyl, Rb=propyl andRc=hydrogen.
 7. A compound as claimed in claim 1 or 6 wherein saidpharmaceutically acceptable salt is selected from a group consisting ofthose made with hydrochloric, hydrobromic, sulfuric, nitric, phosphoricand methanesulfonic acids.
 8. A pharmaceutical composition comprising acompound of claim 1 or a pharmaceutically acceptable salt thereof in anamount sufficient to reduce anxiety in a living mammal in need of suchtreatment in association with a non-toxic pharmaceutically acceptablediluent or carrier
 9. A method of treating anxiety in a living mammalcomprising administering to the mammal an effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt thereof.
 10. A compoundas claimed in claim 1 which in9-amino-2,3-dihydro-2,5-dipropylpyrrolo[3,4-b]quinolin-1-one or apharmaceutically acceptable acid addition salt thereof.